Pyrazolyl-based carboxamides II

ABSTRACT

The invention relates to pyrazolyl-based carboxamide compounds useful as ICRAC inhibitors, to pharmaceutical compositions containing these compounds and to these compounds for the use in the treatment and/or prophylaxis of diseases and/or disorders, in particular inflammatory diseases and/or inflammatory disorders.

This application claims priority to the European patent application EP13000117.5 filed Jan. 10, 2013.

FIELD OF THE INVENTION

The invention relates to biologically active compounds, namelysubstituted pyrazol-3-yl-carboxamides bearing a substituted phenyl or6-membered heteroaryl moiety, useful for inhibition of the CalciumRelease Activated Calcium channel (CRAC) and hence for inhibition of theCalcium Release Activated Calcium current (ICRAC), to pharmaceuticalcompositions containing these compounds and also to these compounds foruse in immuosupression and in the treatment and/or prophylaxis ofconditions, diseases and/or disorders, in particular immune disorders,inflammatory conditions and allergic diseases.

BACKGROUND OF THE INVENTION

Calcium-conducting channels in the plasma membrane can appear verydiverse (Parekh & Putney 2005) including voltage-gated ion channels(VOC's), receptor-operated ion channels (ROC's), but also store-operatedchannels (SOC's; Putney, 1986) that are activated in response to adecrease of the intraluminal Calcium concentration within i.e. theendoplasmic reticulum (ER). The latter have been demonstrated to serveas the main Calcium entry mechanisms in non-excitable cells.

Amongst the distinct SOCs, the CRAC current (ICRAC) is certainlycharacterized best and displays biophysical features such as highselectivity for Calcium ions, low conductance, and inward rectification(Hoth & Penner, 1992; Hoth & Penner, 1993; Parekh & Penner, 1997;Lepple-Wienhues & Cahalan, 1996; Kerschbaum & Cahalan, 1999). There'ssubstantial evidence that the channels conducting CRAC predominantlyrely on two proteins, Orai1 and Stim1 (Roos et al., 2005; Feske et al.,2006; Peinelt et al., 2006). Orai1 constitutes the channel pore withinthe plasma membrane (Prakriya et al., 2006; Vig et al., 2006), whereasStim1 has been demonstrated to function as the sensor of the luminalCalcium concentration (Liou et al., 2005; Zhang et al., 2006).

In a physiological setting, ICRAC is activated in response to theengagement of cell-surface receptors that positively couple tophospholipase C (PLC). PLC increases the concentration of the solublemessenger inositol-1,4,5-trisphosphate (IP3), which opens ERmembrane-resident IP3-receptors. Thus, IP3 triggers the release ofCalcium from internal stores resulting in a drop of the luminal Calciumconcentration (Lewis, 1999), which is sensed by Stim1. The Stim1molecule undergoes conformational changes inducing clustering with otherStim1 molecules just underneath the plasma membrane. At these sites,Stim1 can open the Orai1 pore by bridging the ER-PM gap with itsC-terminal tail (Zhang et al., 2005; Luik et al., 2006; Soboloff et al.2006, Wu et al. 2006; Li et al., 2007).

The above described process serves in signaling pathways of immune cellssuch as lymphocytes and mast cells. I.e. the activation of antigen or Fcreceptors stimulates the release of Calcium from intracellular stores,and subsequent activation of ICRAC that impacts on downstream processessuch as gene expression and cytokine release (Feske, 2007; Gwack et al.,2007; Oh-hora & Rao 2008).

The major contribution ICRAC provides to these signaling events has beenconvincingly demonstrated in patients suffering from severe combinedimmunodeficiency (SCID) due to a defect in T-cell activation. T cellsand fibroblasts from these patients exhibited a strong attenuation ofstore-operated Calcium entry carried by ICRAC (Feske et al., 2006). Thissuggests CRAC channel modulators to serve as treatment in disease statescaused by activated inflammatory cells.

The activation of antigen or Fc receptors stimulates the release ofCalcium from intracellular stores and subsequent, sustained activationof ICRAC. Calcium carried by ICRAC activates calcineurin (CaN), whichdephosphorylates the transcription factor NFAT. Upon dephosphorylation,NFAT shuttles into the nucleus and regulates gene expression in variousways depending on the nature of the stimulus as well as on thecell/tissue type.

NFAT participates in the transactivation of cytokine genes that regulateT-cell proliferation and other genes that control immune responses.Taking into account that the expression of cytokines such as IL-2, IL-4,IL-5, IL-8, IL-13, tumor necrosis factor alpha (TNFα), granulocytecolony-stimulating factor (G-CSF), and gamma-interferon (INFγ) is proneto be controlled via transcriptional elements for NFAT, the impact ofthe ICRAC/CaN/NFAT signaling pathway on pro-inflammatory processesbecomes apparent. The inhibition of this pathway has been demonstratedto be efficacious in patients by the use of drugs such as CsA and FK506,which act by inhibiting CaN.

A hallmark of ICRAC signaling in immune cells is that downstreamprocesses such as gene expression rely on sustained Calcium entry ratherthan transient signals. However, Calcium entry is essential for otherprocesses that can be independent of CaN/NFAT. Direct, Calcium-mediatedrelease of substances (degranulation) such as histamine, heparin, andTNFα occur in i.e. mast cells, and are of rather acute nature. On themolecular level, this already points towards a differentiation potentialfor ICRAC blockers from calcineurin inhibitors.

Recent findings suggest that CRAC channel modulators can serve astreatment in disease states caused by the activation of inflammatorycells without side effects observed under treatments with i.e. steroids.Such diseases may include but are not limited to asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, inflammatory boweldisease, glomerulonephritis, neuroinflammatory diseases such as multiplesclerosis, and disorders of the immune system.

U.S. Pat. No. 6,958,339, WO 2009/076454 A1, WO 2009/089305 A1, and WO2010/122089 A1 each disclose a series of pyrazole carboxamidederivatives that are said to possess CRAC channel inhibitory activitywhich are believed to be useful in the treatment of allergic,inflammatory or autoimmune diseases. Other small molecules possessingstructurally different scaffolds as ICRAC inhibitors are known forinstance from WO2005/009539, WO 2007/087427 A2 and WO 2007/087441 A2.

Pyrazole carboxamides as biologically active compounds are also known inthe art, for instance from EP 1176140 B1, US 2006/0100208 A1, WO2005/016877 A2, WO 2006/076202 A1, WO 2007/002559 A1, WO 2007/024744 A2,WO 2009/011850 A2 and WO 2009/027393.

SUMMARY OF THE INVENTION

The present invention describes a new class of small molecule that isuseful for the inhibition of the calcium release activated calciumchannel current (thereafter ICRAC inhibitors).

It was therefore an object of the invention to provide novel compounds,preferably having advantages over the prior-art compounds. The compoundsshould be suitable in particular as pharmacological active ingredientsin pharmaceutical compositions, preferably in pharmaceuticalcompositions for the treatment and/or prophylaxis of disorders ordiseases which are at least partially mediated by CRAC channels.

This object is achieved by the subject matter described herein.

It has surprisingly been found that the substituted compounds of generalformula (I), as given below, display potent inhibitory activity againstto CRAC channels and are therefore particularly suitable for theprophylaxis and/or treatment of disorders or diseases which are at leastpartially mediated by CRAC channels.

A first aspect of the present invention therefore relates to a compoundof general formula (I),

wherein

-   R¹ denotes    -   C₁₋₄-aliphatic residue, unsubstituted or mono- or        polysubstituted; or    -   C₃₋₆-cycloaliphatic residue or a 3 to 7 membered        heterocycloaliphatic residue, in each case unsubstituted or        mono- or polysubstituted and in each case optionally connected        via a C₁₋₄ aliphatic group, which in turn may be unsubstituted        or mono- or polysubstituted;        -   with the proviso that if R¹ represents a 3 to 7 membered            heterocycloaliphatic residue, said 3 to 7 membered            heterocycloaliphatic residue is connected to the remaining            part of the structure according to general formula (I) via a            carbon atom of the 3 to 7 membered heterocycloaliphatic            residue;-   R² denotes H; F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; R¹³; OH;    O—R¹³; NH₂; N(H)R¹³; N(R¹³)₂;-   U represents C—R⁴ or N or N⁺—O⁻, V represents C—R⁵ or N or N⁺—O⁻, W    represents C—R⁶ or N or N⁺—O⁻, and X represents C—R⁷ or N or N⁺—O⁻,    with the proviso that 0, 1, 2 or 3 of variables T, U, V, W and X    independently of one another represent(s) either N or N⁺—O⁻, whereof    0 or 1 of variables T, U, V, W and X independently of one another    represent(s) N⁺—O⁻ and    with the proviso that at least one of U, V and W does not represent    N,    wherein-   R⁴, R⁵ and R⁶ are independently of one another selected from the    group consisting of H; F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂;    CF₂Cl; CFCl₂; C₁₋₈-aliphatic residue, unsubstituted or mono- or    polysubstituted; C(═O)OH; C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³;    C(═O)—OR¹⁴; C(═O)—N(H)(OH); C(═N—OH)—H; C(═N—OH)—R¹³; C(═N—OH)—R¹⁴;    C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³; C(═N—O—R¹³)—R¹⁴; C(═O)NH₂;    C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴; C(═O)—N(R¹⁴)₂;    C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃; OCF₂H;    OCFH₂; OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴;    O—C(═O)—N(H)R¹³; O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂;    O—C(═O)—N(R¹³)(R¹⁴); O—C(═O)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂;    N(H)R¹⁴; N(R¹⁴)₂; N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴;    NH—C(═O)—R¹³; N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³;    N(R¹³)—S(═O)₂—R¹³; NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴;    N(H)—C(═O)—OR¹³; N(H)—C(═O)—OR¹⁴; N(R¹³)—C(═O)—OR¹³;    N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)R¹³;    N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂; N(H)—C(═O)—N(R¹⁴)₂;    N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));    N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;    N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂;    N(R¹³)—C(═O)—N(R¹³)(R¹⁴); N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³;    SCF₃; S—R¹⁴; S(═O)₂OH; S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴;    S(═O)₂—OR¹³; S(═O)₂—OR¹⁴; S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂;    S(═O)₂—N(H)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴); S(═O)₂—N(R^(a))(R^(b));-   R³ and R⁷ are independently of one another selected from the group    consisting of H; F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl;    CFCl₂; R¹³; R¹⁴; C(═O)OH; C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³;    C(═O)—OR¹⁴; C(═O)—N(H)(OH); C(═N—OH)—H; C(═N—OH)—R¹³; C(═N—OH)—R¹⁴;    C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³; C(═N—O—R¹³)—R¹⁴; C(═O)NH₂;    C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴; C(═O)—N(R¹⁴)₂;    C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃; OCF₂H;    OCFH₂; OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴;    O—C(═O)—N(H)R¹³; O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂;    O—C(═O)—N(R¹³)(R¹⁴); O—C(═o)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂;    N(H)R¹⁴; N(R¹⁴)₂; N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴;    NH—C(═O)—R¹³; N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³;    N(R¹³)—S(═O)₂—R¹³; NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴;    N(H)—C(═O)—OR¹³; N(H)—C(═O)—OR¹⁴; N(R¹³)—C(═O)—OR¹³;    N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)R¹³;    N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂; N(H)—C(═O)—N(R¹⁴)₂;    N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));    N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;    N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂;    N(R¹³)—C(═O)—N(R¹³)(R¹⁴); N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³;    SCF₃; S—R¹⁴; S(═O)₂OH; S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴;    S(═O)₂—OR¹³; S(═O)₂—OR¹⁴; S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂;    S(═O)₂—N(H)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴); S(═O)₂—N(R^(a))(R^(b));    -   with the proviso that R³ does not represent H;-   n represents 0 or 1,-   wherein, if n represents 1, then    -   K represents C—R⁹ or N or N⁺—O⁻,    -   M represents C—R¹⁰ or N or N⁺—O⁻,    -   Q represents C—R¹¹ or N or N⁺—O⁻, and    -   R represents C—R¹² or N or N⁺—O⁻,    -   with the proviso that 0, 1, 2 or 3 of variables K, M, Q and R        independently of one another represent(s) either N or N⁺—O⁻,        whereof 0 or 1 of variables K, M, Q and R independently        represents N⁺—O⁻,-   wherein, if n represents 0, then    -   K represents C—R⁹ or N or N⁺—O⁻ or O or S or NH or        N(C₁₋₄-aliphatic residue),    -   M represents C—R¹⁰ or N or N⁺—O⁻ or O or S or NH or        N(C₁₋₄-aliphatic residue) and    -   Q represents C—R¹¹ or N or N⁺—O⁻ or O or S or NH or        N(C₁₋₄-aliphatic residue),    -   with the proviso that one of K, M and Q represents O or S or NH        or N(C₁₋₄-aliphatic residue) and the remaining of K, M and Q        independently represent C—R⁹, respectively C—R¹⁰, respectively        O—R¹¹ or N or N⁺—O⁻ and    -   with the proviso that 0, 1 or 2 of variables K, M and Q        independently of one another represent either N or N⁺—O⁻,        whereof 0 or 1 of variables K, M and Q represents N⁺—O⁻,        wherein R⁸ is selected from F, Cl, CF₃, CF₂H, CFH₂, CH₃, CN,        OCH₃, OCF₂H, OCFH₂, and OCF₃, and wherein-   R⁹, R¹⁰, R¹¹ and R¹² are independently of one another selected from    the group consisting of H; F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂;    CF₂Cl; CFCl₂; R¹³; R¹⁴; C(═O)OH; C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³;    C(═O)—OR¹⁴; C(═O)—N(H)(OH); C(═N—OH)—H; C(═N—OH)—R¹³; C(═N—OH)—R¹⁴;    C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³; C(═N—O—R¹³)—R¹⁴; C(═O)NH₂;    C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴; C(═O)—N(R¹⁴)₂;    C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃; OCF₂H;    OCFH₂; OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴;    O—C(═O)—N(H)R¹³; O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂;    O—C(═O)—N(R¹³)(R¹⁴); O—C(═O)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂;    N(H)R¹⁴; N(R¹⁴)₂; N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴;    NH—C(═O)—R¹³; N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³;    N(R¹³)—S(═O)₂—R¹³; NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴;    N(H)—C(═O)—OR¹³; N(H)—C(O)—OR¹⁴; N(R¹³)—C(═O)—OR¹³;    N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)R¹³;    N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂; N(H)—C(═O)—N(R¹⁴)₂;    N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));    N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;    N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂;    N(R¹³)—C(═O)—N(R¹³)(R¹⁴); N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³;    SCF₃; S—R¹⁴; S(═O)₂OH; S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴;    S(═O)₂—OR¹³; S(═O)₂—OR¹⁴; S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂;    S(═O)₂—N(FI)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴); S(═O)₂—N(R^(a))(R^(b));    wherein-   each R¹³ independently of each other denotes    -   C₁₋₈-aliphatic residue, unsubstituted or mono- or        polysubstituted;    -   or    -   C₃₋₆-cycloaliphatic residue or 3 to 7 membered        heterocycloaliphatic residue, in each case unsubstituted or        mono- or polysubstituted;    -   or    -   C₃₋₆-cycloaliphatic residue or 3 to 7 membered        heterocycloaliphatic residue, in each case unsubstituted or        mono- or polysubstituted, and in each case connected via a        C₁₋₄-aliphatic residue, unsubstituted or mono- or        polysubstituted;-   each R¹⁴ independently of each other denotes    -   aryl and heteroaryl residue, in each case independently of one        another unsubstituted or mono- or polysubstituted,    -   or    -   aryl and heteroaryl residue, in each case independently of one        another unsubstituted or mono- or polysubstituted and in each        case connected via a C₁₋₄-aliphatic group, unsubstituted or        mono- or polysubstituted;-   R^(a) and R^(b) together with the N-atom connecting them form a 3 to    7 membered heterocyclic residue, unsubstituted or mono- or    polysubstituted;    in which “mono- or polysubstituted” with respect to an “aliphatic    group”, an “aliphatic residue” a “cycloaliphatic residue” and a    “heterocycloaliphatic residue” relates in each case independently of    one another, with respect to the corresponding residues or groups,    to the substitution of one or more hydrogen atoms each independently    of one another by at least one substituent selected from the group    consisting of F; Cl; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;    C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7 membered    heterocyclic residue; aryl; heteroaryl; aryl, heteroaryl,    C₃₋₆-cycloaliphatic residue or 3 to 6 membered heterocycloaliphatic,    each connected via a C₁₋₄-aliphatic group; C(═O)—(C₁₋₈-aliphatic    residue); C(═O)—(C₃₋₆-cycloaliphatic residue); C(═O)-(3 to 7    membered heterocyclic residue); C(═O)-(aryl); C(═O)-(heteroaryl);    C(═O)OH; C(═O)—O(C₁₋₈-aliphatic residue);    C(═O)—O(C₃₋₆-cycloaliphatic residue); C(═O)—O(3 to 7 membered    heterocyclic residue); C(═O)—O(aryl); C(═O)—O(heteroaryl);    C(═O)—NH₂; C(═O)—N(H)(C₁₋₈-aliphatic residue);    C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); C(═O)—N(H)(3 to 7 membered    heterocyclic residue); C(═O)—N(H)(aryl); C(═O)—N(H)(heteroaryl);    C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);    C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);    C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic    residue); C(═O)—N(C₁₋₈-aliphatic residue)(aryl);    C(═O)—N(C₁₋₈-aliphatic residue)-(heteroaryl); OH; ═O;    O—(C₁₋₈-aliphatic residue); O—(C₃₋₆-cycloaliphatic residue); O-(3 to    7 membered heterocyclic residue); O-(aryl); O-(heteroaryl); OCF₃;    OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; O—(C₂₋₄-aliphatic group)-OH;    O—(C₂₋₄-aliphatic group)-O(C₁₋₈-aliphatic residue);    O—C(═O)—(C₁₋₈-aliphatic residue); O—C(═O)—(C₃₋₆-cycloaliphatic    residue); O—C(═O)-(3 to 7 membered heterocyclic residue);    O—C(═O)-(aryl); C(═O)-(heteroaryl); O—C(═O)—NH₂;    O—C(═O)—N(H)(C₁₋₈-aliphatic residue);    O—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); O—C(═O)—N(H)(3 to 7    membered heterocyclic residue); O—C(═O)—N(H)(aryl);    O—C(═O)—N(H)-(heteroaryl); O—C(═O)—N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); O—C(═O)—N(C₁₋₈-aliphatic    residue)-(C₃₋₆-cycloaliphatic residue); O—C(═O)—N(C₁₋₈-aliphatic    residue)(3 to 7 membered heterocyclic residue);    O—C(═O)—N(C₁-aliphatic residue)(aryl); O—C(═O)—N(C₁₋₈-aliphatic    residue)(heteroaryl); NH₂; N(H)(C₁₋₈-aliphatic residue);    N(H)(C₃₋₆-cycloaliphatic residue); N(H)(3 to 7 membered heterocyclic    residue); N(H)(aryl); N(H)(heteroaryl); N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic residue)(3    to 7 membered heterocyclic residue); N(C₁₋₈-aliphatic    residue)(aryl); N(C₁₋₈-aliphatic residue)(heteroaryl);    N(H)—C(═O)—(C₁₋₈-aliphatic residue); N(H)—C(═O)—(C₃₋₆-cycloaliphatic    residue); N(H)—C(═O)-(3 to 7 membered heterocyclic residue);    N(H)—C(═O)-(aryl); N(H)—C(═O)-(heteroaryl); N(C₁₋₈-aliphatic    residue)-C(═O)—(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)-(3 to 7 membered heterocyclic residue);    N(C₁₋₈-aliphatic residue)-C(═O)-(aryl); N(C₁₋₈-aliphatic    residue)-C(═O)-(heteroaryl); N(H)—S(═O)₂—(C₁₋₈-aliphatic residue);    N(H)—S(═O)₂—(C₃₋₆-cycloaliphatic residue); N(H)—S(═O)₂-(3 to 7    membered heterocyclic residue); N(H)—S(═O)₂-(aryl);    N(H)—S(═O)₂-(heteroaryl); N(C₁₋₈-aliphatic    residue)-S(═O)₂—(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)-S(═O)₂—(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-S(═O)₂-(3 to 7 membered heterocyclic residue);    N(C₁₋₈-aliphatic residue)-S(═O)₂-(aryl); N(C₁₋₈-aliphatic    residue)-S(═O)₂-(heteroaryl); N(H)—C(═O)—O(C₁₋₈-aliphatic residue);    N(H)—C(═O)—O(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—O(3 to 7    membered heterocyclic residue); N(H)—C(═O)—O(aryl);    N(H)—C(═O)—O(heteroaryl); N(C₁₋₈-aliphatic    residue)-C(═O)—O(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—O(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—O(3 to 7 membered heterocyclic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—O(aryl); N(C₁₋₈-aliphatic    residue)-C(═O)—O(heteroaryl); N(H)—C(═O)—NH₂;    N(H)—C(═O)—N(H)(C₁₋₈-aliphatic residue);    N(H)—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—N(H)(3 to 7    membered heterocyclic residue); N(H)—C(═O)—N(H)(aryl);    N(H)—C(═O)—N(H)(heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—NH₂;    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₁₋₈-aliphatic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₃₋₆-cycloaliphatic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(3 to 7 membered heterocyclic    residue); N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(aryl);    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(heteroaryl);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic    residue); N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(aryl);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)-(heteroaryl); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered    heterocyclic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(aryl); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(heteroaryl);    S—(C₃₋₆-cycloaliphatic residue); S-(3 to 7 membered heterocyclic    residue); S-(aryl); S-(heteroaryl); SCF₃; S(═O)₂OH;    S(═O)—(C₁₋₈-aliphatic residue); S(═O)—(C₃₋₆-cycloaliphatic residue);    S(═O)-(3 to 7 membered heterocyclic residue); S(═O)-(aryl);    S(═O)-(heteroaryl); S(═O)₂—(C₁₋₈-aliphatic residue);    S(═O)₂—(C₃₋₆-cycloaliphatic residue); S(═O)₂-(3 to 7 membered    heterocyclic residue); S(═O)₂-(aryl); S(═O)₂-(heteroaryl);    S(═O)₂—O(C₁₋₈-aliphatic residue); S(═O)₂—O(C₃₋₆-cycloaliphatic    residue); S(═O)₂—O(3 to 7 membered heterocyclic residue);    S(═O)₂—O(aryl); S(═O)₂—O(heteroaryl); S(═O)₂—N(H)(C₁₋₈-aliphatic    residue); S(═O)₂—N(H)(C₃₋₆-cycloaliphatic residue); S(═O)₂—N(H)(3 to    7 membered heterocyclic residue); S(═O)₂—N(H)(aryl);    S(═O)₂—N(H)(heteroaryl); S(═O)₂—N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); S(═O)₂—N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); S(═O)₂—N(C₁₋₈-aliphatic    residue)(3 to 7 membered heterocyclic residue);    S(═O)₂—N(C₁₋₈-aliphatic residue)(aryl); S(═O)₂—N(C₁₋₈-aliphatic    residue)(heteroaryl);    in which “mono- or polysubstituted” with respect to “aryl” and    “heteroaryl” relates, with respect to the corresponding residues, in    each case independently of one another, to the substitution of one    or more hydrogen atoms each independently of one another by at least    one substituent selected from the group consisting of F; Cl; Br;    NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; C₁₋₈-aliphatic residue;    C₃₋₆-cycloaliphatic residue; 3 to 7 membered heterocyclic residue;    aryl; heteroaryl; aryl, heteroaryl, C₃₋₆-cycloaliphatic residue or 3    to 6 membered heterocycloaliphatic, each connected via a    C₁₋₄-aliphatic group; C(═O)H; C(═O)—(C₁₋₈-aliphatic residue);    C(═O)—(C₃₋₆-cycloaliphatic residue); C(═O)-(3 to 7 membered    heterocyclic residue); C(═O)-(aryl); C(═O)-(heteroaryl); C(═O)OH;    C(═O)—O(C₁₋₈-aliphatic residue); C(═O)—O(C₃₋₆-cycloaliphatic    residue); C(═O)—O(3 to 7 membered heterocyclic residue);    C(═O)—O(aryl); C(═O)—O(heteroaryl); C(═O)—NH₂;    C(═O)—N(H)(C₁₋₈-aliphatic residue); C(═O)—N(H)(C₃₋₆-cycloaliphatic    residue); C(═O)—N(H)(3 to 7 membered heterocyclic residue);    C(═O)—N(H)(aryl); C(═O)—N(H)(heteroaryl); C(═O)—N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); C(═O)—N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); C(═O)—N(C₁₋₈-aliphatic    residue)(3 to 7 membered heterocyclic residue);    C(═O)—N(C₁₋₈-aliphatic residue)(aryl); C(═O)—N(C₁₋₈-aliphatic    residue)(heteroaryl); OH; ═O; O—(C₁₋₈-aliphatic residue);    O—(C₃₋₆-cycloaliphatic residue); O-(3 to 7 membered heterocyclic    residue); O-(aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂Cl;    OCFCl₂; O—(C₂₋₄-aliphatic group)-OH; O—(C₂₋₄-aliphatic    group)-O(C₁₋₈-aliphatic residue); O—C(═O)—(C₁₋₈-aliphatic residue);    O—C(═O)—(C₃₋₆-cycloaliphatic residue); O—C(═O)-(3 to 7 membered    heterocyclic residue); O—C(═O)-(aryl); C(═O)-(heteroaryl);    O—C(═O)—NH₂; O—C(═O)—N(H)(C₁₋₈-aliphatic residue);    O—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); O—C(═O)—N(H)(3 to 7    membered heterocyclic residue); O—C(═O)—N(H)(aryl);    O—C(═O)—N(H)(heteroaryl); O—C(═O)—N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); O—C(═O)—N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); O—C(═O)—N(C₁₋₈-aliphatic    residue)(3 to 7 membered heterocyclic residue);    O—C(═O)—N(C₁₋₈-aliphatic residue)(aryl); O—C(═O)—N(C₁₋₈-aliphatic    residue)(heteroaryl); NH₂; N(H)(C₁₋₈-aliphatic residue);    N(H)(C₃₋₆-cycloaliphatic residue); N(H)(3 to 7 membered heterocyclic    residue); N(H)(aryl); N(H)(heteroaryl); N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic residue)(3    to 7 membered heterocyclic residue); N(C₁₋₈-aliphatic    residue)(aryl); N(C₁₋₈-aliphatic residue)(heteroaryl);    N(H)—C(═O)—(C₁₋₈-aliphatic residue); N(H)—C(═O)—(C₃₋₆-cycloaliphatic    residue); N(H)—C(═O)-(3 to 7 membered heterocyclic residue);    N(H)—C(═O)-(aryl); N(H)—C(═O)-(heteroaryl); N(C₁₋₈-aliphatic    residue)-C(═O)—(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)-(3 to 7 membered heterocyclic residue);    N(C₁₋₈-aliphatic residue)-C(═O)-(aryl); N(C₁₋₈-aliphatic    residue)-C(═O)-(heteroaryl); N(H)—S(═O)₂—(C₁₋₈-aliphatic residue);    N(H)—S(═O)₂—(C₃₋₆-cycloaliphatic residue); N(H)—S(═O)₂-(3 to 7    membered heterocyclic residue); N(H)—S(═O)₂-(aryl);    N(H)—S(═O)₂-(heteroaryl); N(C₁₋₈-aliphatic    residue)-S(═O)₂—(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)-S(═O)₂—(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-S(═O)₂-(3 to 7 membered heterocyclic residue);    N(C₁₋₈-aliphatic residue)S(═O)₂-(aryl); N(C₁₋₈-aliphatic    residue)-S(═O)₂-(heteroaryl); N(H)—C(═O)—O(C₁₋₈-aliphatic residue);    N(H)—C(═O)—O(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—O(3 to 7    membered heterocyclic residue); N(H)—C(═O)—O(aryl);    N(H)—C(═O)—O(heteroaryl); N(C₁₋₈-aliphatic    residue)-C(═O)—O(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—O(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—O(3 to 7 membered heterocyclic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—O(aryl); N(C₁₋₈-aliphatic    residue)-C(═O)—O(heteroaryl); N(H)—C(═O)—NH₂;    N(H)—C(═O)—N(H)(C₁₋₈-aliphatic residue);    N(H)—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—N(H)(3 to 7    membered heterocyclic residue); N(H)—C(═O)—N(H)(aryl);    N(H)—C(═O)—N(H)(heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—NH₂;    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₁₋₈-aliphatic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₃₋₆-cycloaliphatic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(3 to 7 membered heterocyclic    residue); N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(aryl);    N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(heteroaryl);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic    residue); N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(aryl);    N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(heteroaryl); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);    N(C₁₋₈-aliphatic residue)-C(═O)—N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered    heterocyclic residue); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue)(aryl); N(C₁₋₈-aliphatic    residue)-C(═O)—N(C₁₋₈-aliphatic residue) heteroaryl); SH;    S—(C₁₋₈-aliphatic residue); S—(C₃₋₆-cycloaliphatic residue); S-(3 to    7 membered heterocyclic residue); S-(aryl); S-(heteroaryl); SCF₃;    S(═O)₂OH; S(═O)—(C₁₋₈-aliphatic residue); S(═O)—(C₃₋₆-cycloaliphatic    residue); S(═O)-(3 to 7 membered heterocyclic residue);    S(═O)-(aryl); S(═O)-(heteroaryl); S(═O)₂—(C₁₋₈-aliphatic residue);    S(═O)₂—(C₃₋₆-cycloaliphatic residue); S(═O)₂-(3 to 7 membered    heterocyclic residue); S(═O)₂-(aryl); S(═O)₂-(heteroaryl);    S(═O)₂—O(C₁₋₈-aliphatic residue); S(═O)₂—O(C₃₋₆-cycloaliphatic    residue); S(═O)₂—O(3 to 7 membered heterocyclic residue);    S(═O)₂—O(aryl); S(═O)₂—O(heteroaryl); S(═O)₂—N(H)(C₁₋₈-aliphatic    residue); S(═O)₂—N(H)(C₃₋₆-cycloaliphatic residue); S(═O)₂—N(H)(3 to    7 membered heterocyclic residue); S(═O)₂—N(H)(aryl);    S(═O)₂—N(H)(heteroaryl); S(═O)₂—N(C₁₋₈-aliphatic    residue)(C₁₋₈-aliphatic residue); S(═O)₂—N(C₁₋₈-aliphatic    residue)(C₃₋₆-cycloaliphatic residue); S(═O)₂—N(C₁₋₈-aliphatic    residue)(3 to 7 membered heterocyclic residue);    S(═O)₂—N(C₁₋₈-aliphatic residue)(aryl); S(═O)₂—N(C₁₋₈-aliphatic    residue)(heteroaryl);    optionally in the form of a single stereoisomer or a mixture of    stereoisomers, in the form of the free compound and/or a    physiologically acceptable salt thereof and/or a physiologically    acceptable solvate thereof,    with the proviso that the compound according to general formula (I)    does not represent-   N-(2-Cyanophenyl)-5-(2-methoxy-5-methylphenyl)-1-methyl-1H-pyrazole-3-carboxamide,

-   5-(2-Fluoro-4-methoxyphenyl)-N-(2-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxamide,

-   1-Ethyl-5-(2-fluoro-4-methoxyphenyl)-N-(2-fluorophenyl)-1H-pyrazole-3-carboxamide

DETAILED DESCRIPTION

The term “single stereoisomer” preferably means in the sense of thepresent invention an individual enantiomer or diastereomer. The term“mixture of stereoisomers” means in the sense of this invention theracemate and mixtures of enantiomers and/or diastereomers in any mixingratio.

The term “physiologically acceptable salt” preferably comprises in thesense of this invention a salt of at least one compound according to thepresent invention and at least one physiologically acceptable acid orbase.

A physiologically acceptable salt of at least one compound according tothe present invention and at least one physiologically acceptable acidpreferably refers in the sense of this invention to a salt of at leastone compound according to the present invention with at least oneinorganic or organic acid which is physiologically acceptable—inparticular when used in human beings and/or other mammals.

A physiologically acceptable salt of at least one compound according tothe present invention and at least one physiologically acceptable basepreferably refers in the sense of this invention to a salt of at leastone compound according to the present invention as an anion with atleast one preferably inorganic cation, which is physiologicallyacceptable—in particular when used in human beings and/or other mammals.

The term “physiologically acceptable solvate” preferably comprises inthe sense of this invention an adduct of one compound according to thepresent invention and/or a physiologically acceptable salt of at leastone compound according to the present invention with distinct molecularequivalents of one solvent or more solvents.

The terms “C₁₋₈-aliphatic residue” and “C₁₋₄-aliphatic residue” comprisein the sense of this invention acyclic saturated or unsaturatedaliphatic hydrocarbon residues, which can be branched or unbranched andalso unsubstituted or mono- or polysubstituted, which contain 1 to 8 or1 to 4 carbon atoms respectively, i.e. C₁₋₈-alkanyls (C₁₋₈-alkyls),C₂₋₈-alkenyls and C₂₋₈-alkynyls as well as C₁₋₄-alkanyls (C₁₋₄-alkyls),C₂₋₄-alkenyls and C₂₋₄-alkynyls, respectively. Alkenyls comprise atleast one C—C-double bond (a C═C-bond) and alkynyls comprise at leastone C—C triple bond (a C≡C-bond). Preferably, -aliphatic residues areselected from the group consisting of alkanyl (alkyl) and alkenylresidues, more preferably are alkanyl (alkyl) residues. Hence, preferred“C₁₋₈-aliphatic residue” is “C₁₋₈-alkyl” and preferred “C₁₋₄-aliphaticresidue” is “C₁₋₄-alkyl”. Preferred C₁₋₈-alkyl residues are selectedfrom the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl,isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, n-heptyl and n-octyl. Preferred C₁₋₄-alkyl residues areselected from the group consisting of methyl, ethyl, n-propyl, 2-propyl,n-butyl, isobutyl, sec.-butyl and tert.-butyl. Preferred C₂₋₈-alkenylresidues are selected from the group consisting of ethenyl (vinyl),propenyl (—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)CH₃), butenyl, pentenyl,hexenyl heptenyl and octenyl. Preferred C₂₋₄ alkenyl residues areselected from the group consisting of ethenyl (vinyl), propenyl(—CH₂CH═CH₂, —CH═CHCH₃, —C(═CH₂)CH₃) and butenyl. Preferred C₂₋₈ alkynylresidues are selected from the group consisting of ethynyl, propynyl(—CH₂—C≡CH, —C≡C—CH₃), butynyl, pentynyl, hexynyl, heptynyl and octynyl.Preferred C₂₋₄-alkynyl residues are selected from the group consistingof ethynyl, propynyl (—CH₂—C≡CH, —C≡C—CH₃) and butynyl.

The term “C₃₋₆-cycloaliphatic residue” means for the purposes of thisinvention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbonatoms, wherein the hydrocarbons in each case can be saturated orunsaturated (but not aromatic), unsubstituted or mono- orpolysubstituted. The-cycloaliphatic residues can be bound to therespective superordinate general structure via any desired and possiblering member of the-cycloaliphatic residue. The-cycloaliphatic residuescan also be condensed with further saturated, (partially) unsaturated,(hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. withcycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residues, whichin each case can in turn be unsubstituted or mono- or polysubstituted.Preferred C₃₋₆-cycloaliphatic residues are selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopentenyl and cyclohexenyl, in particular cyclopropyl.

The terms “3 to 7 membered heterocycloaliphatic residue” or“3-7-membered heterocycloaliphatic residue”, mean for the purposes ofthis invention heterocycloaliphatic saturated or unsaturated (but notaromatic) residues having 3 to 6, i.e. 3, 4, 5 or 6 ring members, inwhich in each case at least one, if appropriate also two, three or fourcarbon atoms are replaced by a heteroatom or a heteroatom group eachselected independently of one another from the group consisting of O, S,S(═O), S(═O)₂, N, NH and N(C₁₋₆-alkyl) such as N(CH₃), wherein the ringmembers can be unsubstituted or mono- or polysubstituted. The 3 to 7membered heterocycloaliphatic residue residues can also be condensedwith further saturated, (partially) unsaturated, (hetero)cyclic,aromatic or heteroaromatic ring systems, i.e. with cycloaliphatic,heterocycloaliphatic, aryl or heteroaryl residues, which in each casecan in turn be unsubstituted or mono- or polysubstituted. Theheterocycloaliphatic residue can be bound to the superordinate generalstructure via any desired and possible ring member of theheterocycloaliphatic residue if not indicated otherwise.

The term “aryl” means for the purpose of this invention aromatichydrocarbons having 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12, 13 or 14 ringmembers, preferably having 6 to 10, i.e. 6, 7, 8, 9 or 10 ring members,including phenyls and naphthyls. Each aryl residue can be unsubstitutedor mono- or polysubstituted, wherein the aryl substituents can be thesame or different and in any desired and possible position of the aryl.The aryl can be bound to the superordinate general structure via anydesired and possible ring member of the aryl residue. The aryl residuescan also be condensed with further saturated, (partially) unsaturated,(hetero)cycloaliphatic, aromatic or heteroaromatic ring systems, i.e.with a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue,which can in turn be unsubstituted or mono- or polysubstituted. Examplesof condensed aryl residues are benzodioxolanyl and benzodioxanyl.Preferably, aryl is selected from the group consisting of phenyl,1-naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which can berespectively unsubstituted or mono- or polysubstituted. A particularlypreferred aryl is phenyl, unsubstituted or mono- or polysubstituted.

The term “heteroaryl” for the purpose of this invention represents a 5or 6-membered cyclic aromatic residue containing at least 1, ifappropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms areeach selected independently of one another from the group S, N and O andthe heteroaryl residue can be unsubstituted or mono- or polysubstituted;in the case of substitution on the heteroaryl, the substituents can bethe same or different and be in any desired and possible position of theheteroaryl. The binding to the superordinate general structure can becarried out via any desired and possible ring member of the heteroarylresidue if not indicated otherwise. The heteroaryl can also be part of abi- or polycyclic system having up to 14 ring members, wherein the ringsystem can be formed with further saturated, (partially) unsaturated,(hetero)cycloaliphatic or aromatic or heteroaromatic rings, i.e. with acycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue, whichcan in turn be unsubstituted or mono- or polysubstituted. It ispreferable for the heteroaryl residue to be selected from the groupconsisting of benzofuranyl, benzoimidazolyl, benzothienyl,benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl,benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl,dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl,imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl,isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl,phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl,purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl,thiazolyl, thiadiazolyl and triazinyl.

The term “connected via a C₁₋₄-aliphatic group” with respect to residuesas aryl, heteroaryl, heterocycloaliphatic residue and-cycloaliphaticresidue mean for the purpose of the invention that these residues havethe above-defined meanings and that each of these residues is bound tothe respective superordinate general structure via a C₁₋₄-aliphaticgroup. The C₁₋₄-aliphatic group can in all cases be branched orunbranched, unsubstituted or mono- or polysubstituted. TheC₁₋₄-aliphatic group can in all cases be furthermore saturated orunsaturated, i.e. can be a C₁₋₄-alkylene group, a C₂₋₄-alkenylene groupor a C₂₋₄-alkynylene group. Preferably, the C₁₋₄-aliphatic group is aC₁₋₄-alkylene group or a C₂₋₄-alkenylene group, more preferably aC₁₋₄-alkylene group. Preferred C₁₋₄-alkylene groups are selected fromthe group consisting of —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂CH₂CH₂—,—CH(CH₃)CH₂—, —CH(CH₂CH₃)—, —CH₂(CH₂)₂CH₂—, —CH(CH₃)CH₂CH₂—,—CH₂CH(CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —CH(CH₂CH₃)CH₂—, —C(CH₃)₂CH₂—,—CH(CH₂CH₂CH₃)— and —C(CH₃)(CH₂CH₃)—. Preferred C₂₋₄-alkenylene groupsare selected from the group consisting of —CH═CH—, —CH═CHCH₂—,—C(CH₃)═CH₂—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH═CH—CH═CH—,—C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —C(CH₃)═C(CH₃)— and —C(CH₂CH₃)═CH—.Preferred C₂₋₄-alkynylene groups are selected from the group consistingof —C≡C—, —C≡CCH₂—, —C≡C—CH₂—CH₂—, —C≡C—CH(CH₃)—, —CH₂—C≡C—CH₂— and—C≡C—C≡C—.

In relation to the terms “aliphatic residue” and “aliphatic group”, inparticular “alkyl” and “alkylene”, as well as “aliphatic group”,“cycloaliphatic residue” and “heterocycloaliphatic residue”, the term“mono- or polysubstituted” refers in the sense of this invention, withrespect to the corresponding residues or groups, to the singlesubstitution or multiple substitution, e.g. disubstitution,trisubstitution, tetrasubstitution, or pentasubstitution, of one or morehydrogen atoms each independently of one another by at least onesubstituent selected from the group consisting of F; Cl; CN; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue;3 to 7 membered heterocyclic residue; aryl; heteroaryl; aryl,heteroaryl, C₃₋₆-cycloaliphatic residue or 3 to 6 memberedheterocycloaliphatic, each connected via a C₁₋₄-aliphatic group;C(═O)—(C₁₋₈-aliphatic residue); C(═O)—(C₃₋₆-cycloaliphatic residue);C(═O)-(3 to 7 membered heterocyclic residue); C(═O)-(aryl);C(═O)-(heteroaryl); C(═O)OH; C(═O)—O(C₁₋₈-aliphatic residue);C(═O)—O(C₃₋₆-cycloaliphatic residue); C(═O)—O(3 to 7 memberedheterocyclic residue); C(═O)—O(aryl); C(═O)—O(heteroaryl); C(═O)—NH₂;C(═O)—N(H)(C₁₋₈-aliphatic residue); C(═O)—N(H)(C₃₋₆-cycloaliphaticresidue); C(═O)—N(H)(3 to 7 membered heterocyclic residue);C(═O)—N(H)(aryl); C(═O)—N(H)-(heteroaryl); C(═O)—N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); C(═O)—N(C₁₋₈-aliphaticresidue)(C₃₋₆-cycloaliphatic residue); C(═O)—N(C₁₋₈-aliphatic residue)(3to 7 membered heterocyclic residue); C(═O)—N(C₁₋₈-aliphaticresidue)(aryl); C(═O)—N(C₁₋₈-aliphatic residue)(heteroaryl); OH; ═O;O—(C₁₋₈-aliphatic residue); O—(C₃₋₆-cycloaliphatic residue); O-(3 to 7membered heterocyclic residue); O-(aryl); O-(heteroaryl); OCF₃; OCF₂H;OCFH₂; OCF₂Cl; OCFCl₂; O—C(═O)—(C₁₋₈-aliphatic residue);O—C(═O)—(C₃₋₆-cycloaliphatic residue); O—C(═O)-(3 to 7 memberedheterocyclic residue); O—C(═O)-(aryl); C(═O)-(heteroaryl); O—C(═O)—NH₂;O—C(═O)—N(H)(C₁₋₈-aliphatic residue); O—C(═O)—N(H)(C₃₋₆-cycloaliphaticresidue); O—C(═O)—N(H)(3 to 7 membered heterocyclic residue);O—C(═O)—N(H)(aryl); O—C(═O)—N(H)(heteroaryl); O—C(═O)—N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); O—C(═O)—N(C₁₋₈-aliphaticresidue)(C₃₋₆-cycloaliphatic residue); O—C(═O)—N(C₁₋₈-aliphaticresidue)(3 to 7 membered heterocyclic residue); O—C(═O)—N(C₁₋₈-aliphaticresidue)(aryl); O—C(═O)—N(C₁₋₈-aliphatic residue) (heteroaryl); NH₂;N(H)(C₁₋₈-aliphatic residue); N(H)(C₃₋₆-cycloaliphatic residue); N(H)(3to 7 membered heterocyclic residue); N(H)(aryl); N(H)(heteroaryl);N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphaticresidue)(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic residue)(3 to 7membered heterocyclic residue); N(C₁₋₈-aliphatic residue)(aryl);N(C₁₋₈-aliphatic residue)(heteroaryl); N(H)—C(═O)—(C₁₋₈-aliphaticresidue); N(H)—C(═O)—(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)-(3 to 7membered heterocyclic residue); N(H)—C(═O)-(aryl);N(H)—C(═O)-(heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—(C₁₋₈-aliphaticresidue); N(C₁₋₈-aliphatic residue)-C(═O)—(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)-(3 to 7 membered heterocyclic residue);N(C₁₋₈-aliphatic residue)-C(═O)-(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)-(heteroaryl); N(H)—S(═O)₂—(C₁₋₈-aliphatic residue);N(H)—S(═O)₂—(C₃₋₆-cycloaliphatic residue); N(H)—S(═O)₂-(3 to 7 memberedheterocyclic residue); N(H)—S(═O)₂-(aryl); N(H)—S(═O)₂-(heteroaryl);N(C₁₋₈-aliphatic residue)-S(═O)₂—(C₁₋₈-aliphatic residue);N(C₁₋₈-aliphatic residue)-S(═O)₂—(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-S(═O)₂-(3 to 7 membered heterocyclic residue);N(C₁₋₈-aliphatic residue)-S(═O)₂-(aryl); N(C₁₋₈-aliphaticresidue)-S(═O)₂-(heteroaryl); N(H)—C(═O)—O(C₁₋₈-aliphatic residue);N(H)—C(═O)—O(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—O(3 to 7 memberedheterocyclic residue); N(H)—C(═O)—O(aryl); N(H)—C(═O)—O(heteroaryl);N(C₁₋₈-aliphatic residue)-C(═O)—O(C₁₋₈-aliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—O(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—O(3 to 7 membered heterocyclic residue);N(C₁₋₈-aliphatic residue)-C(═O)—O(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)—O(heteroaryl); N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)(C₁₋₈-aliphatic residue);N(H)—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—N(H)(3 to 7membered heterocyclic residue); N(H)—C(═O)—N(H)(aryl);N(H)—C(═O)—N(H)(heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—NH₂;N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₁₋₈-aliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(3 to 7 membered heterocyclicresidue); N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)—N(H)(heteroaryl); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(3 to 7 membered heterocyclic residue);N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(aryl); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphaticresidue)-C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7membered heterocyclic residue); N(C₁₋₈-aliphaticresidue)-C(═O)—N(C₁₋₈-aliphatic residue)(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)—N(C₁₋₈-aliphatic residue)(heteroaryl);S—(C₃₋₆-cycloaliphatic residue); S-(3 to 7 membered heterocyclicresidue); S-(aryl); S-(heteroaryl); SCF₃; S(═O)₂OH;S(═O)—(C₁₋₈-aliphatic residue); S(═O)—(C₃₋₆-cycloaliphatic residue);S(═O)-(3 to 7 membered heterocyclic residue); S(═O)-(aryl);S(═O)-(heteroaryl); S(═O)₂—(C₁₋₈-aliphatic residue);S(═O)₂—(C₃₋₆-cycloaliphatic residue); S(═O)₂-(3 to 7 memberedheterocyclic residue); S(═O)₂-(aryl); S(═O)₂-(heteroaryl);S(═O)₂—O(C₁₋₈-aliphatic residue); S(═O)₂—O(C₃₋₆-cycloaliphatic residue);S(═O)₂—O(3 to 7 membered heterocyclic residue); S(═O)₂—O(aryl);S(═O)₂—O(heteroaryl); S(═O)₂—N(H)(C₁₋₈-aliphatic residue);S(═O)₂—N(H)(C₃₋₆-cycloaliphatic residue); S(═O)₂—N(H)(3 to 7 memberedheterocyclic residue); S(═O)₂—N(H)(aryl); S(═O)₂—N(H)(heteroaryl);S(═O)₂—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);S(═O)₂—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);S(═O)₂—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic residue);S(═O)₂—N(C₁₋₈-aliphatic residue)(aryl); S(═O)₂—N(C₁₋₈-aliphaticresidue)(heteroaryl).

The term “polysubstituted” with respect to polysubstituted residues andgroups includes the poly-substitution of these residues and groupseither on different or on the same atoms, for example tri-substituted onthe same carbon atom, as in the case of CF₃, CH₂CF₃ or1,1-difluorocyclohexyl, or at various points, as in the case ofCH(OH)—CH═CH—CHCl₂ or 1-chloro-3-fluorocyclohexyl. A substituent can ifappropriate for its part in turn be mono- or polysubstituted. Themultiple substitution can be carried out using the same or usingdifferent substituents.

Preferred substituents of “aliphatic residue” and “aliphatic group”, inparticular “alkyl” and “alkylene”, as well as of “aliphatic group”,“cycloaliphatic residue” and “heterocycloaliphatic residue” are selectedfrom the group consisting of F; Cl; CN; ═O; CF₃; CF₂H; CFH₂; CF₂Cl;CFCl₂; C₁₋₄-alkyl; (C₂₋₄-aliphatic group)-OH; C(═O)—H; C(═O)—C₁₋₄-alkyl;C(═O)—OH; C(═O)—O—C₁₋₄-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂;C(═O)—N(H)(C₁₋₄-alkyl); C(═O)—N(C₁₋₄-alkyl)₂; OH; OCF₃; OCF₂H; OCFH₂;OCF₂Cl; OCFCl₂; O—C₁₋₄-alkyl; O—C(═O)—C₁₋₄-alkyl; O—C(═O)—O—C₁₋₄-alkyl;O—(C═O)—N(H)(C₁₋₄-alkyl); O—C(═O)—N(C₁₋₄-alkyl)₂; O—S(═O)₂—C₁₋₄-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₄-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₄-alkyl); O—S(═O)₂—N(C₁₋₄-alkyl)₂; NH₂;N(H)(C₁₋₄-alkyl); N(C₁₋₄-alkyl)₂; N(H)—C(═O)—C₁₋₄-alkyl;N(H)—C(═O)—O—C₁₋₄-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₄-alkyl);N(H)—C(═O)—N(C₁₋₄-alkyl)₂; N(C₁₋₄-alkyl)-C(═O)—C₁₋₄-alkyl;N(C₁₋₄-alkyl)-C(═O)—O—C₁₋₄-alkyl; N(C₁₋₄-alkyl)-C(═O)—NH₂;N(C₁₋₄-alkyl)-C(═O)—N(H)(C₁₋₄-alkyl);N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂; N(H)—S(═O)₂—OH;N(H)—S(═O)₂—C₁₋₄-alkyl; N(H)—S(═O)₂—O—C₁₋₄-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₄-alkyl); N(H)—S(═O)₂—N(C₁₋₄-alkyl)₂;N(C₁₋₄-alkyl)-S(═O)₂—OH; N(C₁₋₄-alkyl)-S(═O)₂—C₁₋₄-alkyl;N(C₁₋₄-alkyl)-S(═O)₂—O—C₁₋₄-alkyl; N(C₁₋₄-alkyl)-S(═O)₂—NH₂;N(C₁₋₄-alkyl)-S(═O)₂—N(H)(C₁₋₄-alkyl);N(C₁₋₄-alkyl)-S(═O)₂—N(C₁₋₄-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₄-alkyl; S(═O)—C₁₋₄-alkyl; S(═O)₂—C₁₋₄-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₄-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₄-alkyl); andS(═O)₂—N(C₁₋₄-alkyl)₂.

Particularly preferred substituents of “aliphatic residue” and“aliphatic group”, in particular “alkyl” and “alkylene”, as well as of“aliphatic group”, “cycloaliphatic residue” and “heterocycloaliphaticresidue” are selected from the group consisting of F; Cl; CF₃; CN; ═O;C₁₋₄-alkyl; (C₂₋₄-aliphatic group)-OH; C(═O)—H; C(═O)—C₁₋₄-alkyl;C(═O)—OH; C(═O)—O—C₁₋₄-alkyl; C(═O)—NH₂; C(═O)—N(H)(C₁₋₄-alkyl);C(═O)—N(C₁₋₄-alkyl)₂; OH; O—C₁₋₄-alkyl; O—C(═O)—C₁₋₄-alkyl; OCF₃; NH₂;N(H)(C₁₋₄-alkyl); N(C₁₋₄-alkyl)₂; N(H)—O(═O)—C₁₋₄-alkyl;N(H)—S(═O)₂—C₁₋₄-alkyl; N(C₁₋₄-alkyl)-S(═O)₂—C₁₋₄-alkyl; N(H)—O(═O)—NH₂;N(H)—O(═O)—N(H)(C₁₋₄-alkyl); N(H)—O(═O)—N(C₁₋₄-alkyl)₂; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₄-alkyl); N(H)—S(═O)₂—N(C₁₋₄-alkyl)₂;N(C₁₋₄-alkyl)-S(═O)₂—NH₂; N(C₁₋₄-alkyl)-S(═O)₂—N(H)(C₁₋₄-alkyl);N(C₁₋₄-alkyl)-S(═O)₂—N(C₁₋₄-alkyl)₂; SH; SCF₃; S—C₁₋₄-alkyl;S(═O)₂C₁₋₄-alkyl; S(═O)₂OH; S(═O)₂O—C₁₋₄-alkyl and S(═O)₂—NH₂;S(═O)₂—N(H)(C₁₋₄-alkyl); and S(═O)₂—N(C₁₋₄-alkyl)₂.

More preferred substituents of “aliphatic residue” and “aliphaticgroup”, in particular “alkyl” and “alkylene”, as well as of “aliphaticgroup”, “cycloaliphatic residue” and “heterocycloaliphatic residue” areselected from the group consisting of F; Cl; CF₃; CN; ═O; C₁₋₄-alkyl;(C₂₋₄-aliphatic group)-OH; C(═O)—C₁₋₄-alkyl; C(═O)—OH;C(═O)—O—C₁₋₄-alkyl; C(═O)—NH₂; C(═O)—N(H)(C₁₋₄-alkyl);C(═O)—N(C₁₋₄-alkyl)₂; OH; O—C₁₋₄-alkyl; O—C(═O)—C₁₋₄-alkyl; OCF₃; NH₂;N(H)(C₁₋₄-alkyl); N(C₁₋₄-alkyl)₂; N(H)—C(═O)—C₁₋₄-alkyl;N(H)—S(═O)₂—C₁₋₄-alkyl; N(C₁₋₄-alkyl)-S(═O)₂—C₁₋₄-alkyl; N(H)—C(═O)—NH₂;N(H)—O(═O)—N(H)(C₁₋₄-alkyl); N(H)—C(═O)—N(C₁₋₄-alkyl)₂;N(C₁₋₄-alkyl)-S(═O)₂—NH₂; N(C₁₋₄-alkyl)-S(═O)₂—N(H)(C₁₋₄-alkyl);N(C₁₋₄-alkyl)-S(═O)₂—N(C₁₋₄-alkyl)₂; S(═O)₂C₁₋₄-alkyl; S(═O)₂OH;S(═O)₂O—C₁₋₄-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₄-alkyl) andS(═O)₂—N(C₁₋₄-alkyl)₂.

Most preferred substituents of “aliphatic residue” and “aliphaticgroup”, in particular “alkyl” and “alkylene” are selected from the groupconsisting of F; Cl; CF₃; C(═O)—OH; C(═O)—NH₂; C(═O)—N(H)(C₁₋₄-alkyl);C(═O)—N(C₁₋₄-alkyl)₂; OH; O—C₁₋₄-alkyl; NH₂; N(H)(C₁₋₄-alkyl);N(C₁₋₄-alkyl)₂; N(H)—O(═O)—C₁₋₄-alkyl; N(H)—S(═O)₂—C₁₋₄-alkyl;N(C₁₋₄-alkyl)-S(═O)₂—C₁₋₄-alkyl; N(H)—S(═O)₂—NH₂; S(═O)₂—C₁₋₄-alkyl,S(═O)₂—NH₂, S(═O)₂—N(C₁₋₄-alkyl)₂ and S(═O)₂—N(H)(C₁₋₄-alkyl).

Particularly preferred substituents of “cycloaliphatic residue” and“heterocycloaliphatic residue” are selected from the group consisting ofF; Cl; CF₃; CN; ═O; C₁₋₄-alkyl; CO₂H; C(═O)O—C₁₋₄-alkyl; CONH₂;C(═O)NH—C₁₋₄-alkyl; C(═O)N(C₁₋₄-alkyl)₂; OH; O—C₁₋₄-alkyl; OCF₃;O—C(═O)—C₁₋₄-alkyl; NH₂; NH—C₁₋₄-alkyl; N(C₁₋₄-alkyl)₂;NH—C(═O)—C₁₋₄-alkyl; N(C₁₋₄-alkyl)-O(═O)—C₁₋₄-alkyl; S(═O)₂—C₁₋₄-alkyl;S(═O)₂—NH₂, S(═O)₂—N(C₁₋₄-alkyl)₂ and S(═O)₂—N(H)—C₁₋₄-alkyl.

In relation to the terms “aryl” and “heteroaryl”, the term “mono- orpolysubstituted” refers in the sense of this invention, with respect tothe corresponding residues or groups, to the single substitution ormultiple substitution, e.g. disubstitution, trisubstitution,tetrasubstitution, or pentasubstitution, of one or more hydrogen atomseach independently of one another by at least one substituent selectedfrom the group consisting of F; Cl; Br; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl;CFCl₂; C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocyclic residue; aryl; heteroaryl; aryl, heteroaryl,C₃₋₆-cycloaliphatic residue or 3 to 6 membered heterocycloaliphatic,each connected via a C₁₋₄-aliphatic group; C(═O)H; C(═O)—(C₁₋₈-aliphaticresidue); C(═O)—(C₃₋₆-cycloaliphatic residue); C(═O)-(3 to 7 memberedheterocyclic residue); C(═O)-(aryl); C(═O)-(heteroaryl); C(═O)OH;C(═O)—O(C₁₋₈-aliphatic residue); C(═O)—O(C₃₋₆-cycloaliphatic residue);C(═O)—O(3 to 7 membered heterocyclic residue); C(═O)—O(aryl);C(═O)—O(heteroaryl); C(═O)—NH₂; C(═O)—N(H)(C₁₋₈-aliphatic residue);C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); C(═O)—N(H)(3 to 7 memberedheterocyclic residue); C(═O)—N(H)(aryl); C(═O)—N(H)(heteroaryl);C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic residue);C(═O)—N(C₁₋₈-aliphatic residue)(aryl); C(═O)—N(C₁₋₈-aliphaticresidue)(heteroaryl); OH; ═O; O—(C₁₋₈-aliphatic residue);O—(C₃₋₆-cycloaliphatic residue); O-(3 to 7 membered heterocyclicresidue); O-(aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C(═O)—(C₁₋₈-aliphatic residue); O—C(═O)—(C₃₋₆-cycloaliphatic residue);O—C(═O)-(3 to 7 membered heterocyclic residue); O—C(═O)-(aryl);C(═O)-(heteroaryl); O—C(═O)—NH₂; O—C(═O)—N(H)(C₁₋₈-aliphatic residue);O—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); O—C(═O)—N(H)(3 to 7 memberedheterocyclic residue); O—C(═O)—N(H)(aryl); O—C(═O)—N(H)(heteroaryl);O—C(═O)—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);O—C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);O—C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic residue);O—C(═O)—N(C₁₋₈-aliphatic residue)-(aryl); O—C(═O)—N(C₁₋₈-aliphaticresidue)(heteroaryl); NH₂; N(H)(C₁₋₈-aliphatic residue);N(H)(C₃₋₆-cycloaliphatic residue); N(H)(3 to 7 membered heterocyclicresidue); N(H)(aryl); N(H)(heteroaryl); N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphaticresidue)(C₃₋₆-cycloaliphatic residue); N(C₁₋₈-aliphatic residue)(3 to 7membered heterocyclic residue); N(C₁₋₈-aliphatic residue) (aryl);N(C₁₋₈-aliphatic residue)(heteroaryl); N(H)—C(═O)—(C₁₋₈-aliphaticresidue); N(H)—C(═O)—(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)-(3 to 7membered heterocyclic residue); N(H)—C(═O)-(aryl);N(H)—C(═O)-(heteroaryl); aliphatic residue)-C(═O)—(C₁₋₈-aliphaticresidue); N(C₁₋₈-aliphatic residue)-C(═O)—(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)-(3 to 7 membered heterocyclic residue);N(C₁₋₈-aliphatic residue)-C(═O)-(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)-(heteroaryl); N(H)—S(═O)₂—(C₁₋₈-aliphatic residue);N(H)—S(═O)₂—(C₃₋₆-cycloaliphatic residue); N(H)—S(═O)₂-(3 to 7 memberedheterocyclic residue); N(H)—S(═O)₂-(aryl); N(H)—S(═O)₂-(heteroaryl);N(C₁₋₈-aliphatic residue)-S(═O)₂—(C₁₋₈-aliphatic residue);N(C₁₋₈-aliphatic residue)-S(═O)₂—(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-S(═O)₂-(3 to 7 membered heterocyclic residue);N(C₁₋₈-aliphatic residue)-S(═O)₂-(aryl); N(C₁₋₈-aliphaticresidue)-S(═O)₂-(heteroaryl); N(H)—C(═O)—O(C₁₋₈-aliphatic residue);N(H)—C(═O)—O(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—O(3 to 7 memberedheterocyclic residue); N(H)—C(═O)—O(aryl); N(H)—C(═O)—O(heteroaryl);N(C₁₋₈-aliphatic residue)-C(═O)—O(C₁₋₈-aliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—O(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—O(3 to 7 membered heterocyclic residue);N(C₁₋₈-aliphatic residue)-C(═O)—O(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)—O(heteroaryl); N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)(C₁₋₈-aliphatic residue);N(H)—C(═O)—N(H)(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—N(H)(3 to 7membered heterocyclic residue); N(H)—C(═O)—N(H)(aryl);N(H)—C(═O)—N(H)(heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—NH₂;N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₁₋₈-aliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(3 to 7 membered heterocyclicresidue); N(C₁₋₈-aliphatic residue)-C(═O)—N(H)(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)—N(H)(heteroaryl); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(C₃₋₆-cycloaliphatic residue); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue)(3 to 7 membered heterocyclic residue);N(H)—C(═O)—N(C₁₋₈-aliphatic residue)(aryl); N(H)—C(═O)—N(C₁₋₈-aliphaticresidue) (heteroaryl); N(C₁₋₈-aliphatic residue)-C(═O)—N(C₁₋₈-aliphaticresidue)(C₁₋₈-aliphatic residue); N(C₁₋₈-aliphaticresidue)-C(═O)—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);N(C₁₋₈-aliphatic residue)-C(═O)—N(C₁₋₈-aliphatic residue)(3 to 7membered heterocyclic residue); N(C₁₋₈-aliphaticresidue)-C(═O)—N(C₁₋₈-aliphatic residue)(aryl); N(C₁₋₈-aliphaticresidue)-C(═O)—N(C₁₋₈-aliphatic residue) heteroaryl); SH;S—(C₁₋₈-aliphatic residue); S—(C₃₋₆-cycloaliphatic residue); S-(3 to 7membered heterocyclic residue); S-(aryl); S-(heteroaryl); SCF₃;S(═O)₂OH; S(═O)—(C₁₋₈-aliphatic residue); S(═O)—(C₃₋₆-cycloaliphaticresidue); S(═O)-(3 to 7 membered heterocyclic residue); S(═O)-(aryl);S(═O)-(heteroaryl); S(═O)₂—(C₁₋₈-aliphatic residue);S(═O)₂—(C₃₋₆-cycloaliphatic residue); S(═O)₂-(3 to 7 memberedheterocyclic residue); S(═O)₂-(aryl); S(═O)₂-(heteroaryl);S(═O)₂—O(C₁₋₈-aliphatic residue); S(═O)₂—O(C₃₋₆-cycloaliphatic residue);S(═O)₂—O(3 to 7 membered heterocyclic residue); S(═O)₂—O(aryl);S(═O)₂—O(heteroaryl); S(═O)₂—N(H)(C₁₋₈-aliphatic residue);S(═O)₂—N(H)(C₃₋₆-cycloaliphatic residue); S(═O)₂—N(H)(3 to 7 memberedheterocyclic residue); S(═O)₂—N(H)(aryl); S(═O)₂—N(H)(heteroaryl);S(═O)₂—N(C₁₋₈-aliphatic residue)(C₁₋₈-aliphatic residue);S(═O)₂—N(C₁₋₈-aliphatic residue)(C₃₋₆-cycloaliphatic residue);S(═O)₂—N(C₁₋₈-aliphatic residue)(3 to 7 membered heterocyclic residue);S(═O)₂—N(C₁₋₈-aliphatic residue)(aryl); S(═O)₂—N(C₁₋₈-aliphaticresidue)(heteroaryl).

Preferred substituents of “aryl” and “heteroaryl” are selected from thegroup consisting of F; Cl; Br; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;C₁₋₄-alkyl; aryl; heteroaryl; C₃₋₆-cycloaliphatic residue; 3 to 6membered heterocycloaliphatic residue; aryl, heteroaryl,C₃₋₆-cycloaliphatic residue or 3 to 6 membered heterocycloaliphatic,each connected via a C₁₋₄-aliphatic group; C(═O)—H; C(═O)—C₁₋₄-alkyl;C(═O)aryl; C(═O)heteroaryl; C(═O)—OH; C(═O)—O—C₁₋₄-alkyl; C(═O)O-aryl;C(═O)O-heteroaryl; CO—NH₂; C(═O)—N(H)C₁₋₄-alkyl; C(═O)—N(C₁₋₄-alkyl)₂;C(═O)NH-aryl; C(═O)N(aryl)₂; C(═O)NH-heteroaryl; C(═O)—N(heteroaryl)₂;C(═O)N(C₁₋₄-alkyl)(aryl); C(═O)N(C₁₋₄-alkyl)(heteroaryl);C(═O)N(heteroaryl)(aryl); OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₄-alkyl; O-benzyl; O-aryl; O-heteroaryl; O—C(═O)—C₁₋₄-alkyl;O—C(═O)aryl; O—C(═O)heteroaryl; O—C(═O)—O—C₁₋₄-alkyl;O—(C═O)—N(H)C₁₋₄-alkyl; O—C(═O)—N(C₁₋₄-alkyl)₂; O—S(═O)₂—C₁₋₄-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₄-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)C₁₋₄-alkyl; O—S(═O)₂—N(C₁₋₄-alkyl)₂; NH₂; N(H)C₁₋₄-alkyl;N(C₁₋₄-alkyl)₂; N(H)—C(═O)—C₁₋₄-alkyl; N(H)—C(═O)-aryl;N(H)—C(═O)-heteroaryl; N(H)—C(═O)—O—C₁₋₄-alkyl; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)C₁₋₄-alkyl; N(H)—C(═O)—N(C₁₋₄-alkyl)₂;N(C₁₋₄-alkyl)-C(═O)C₁₋₄-alkyl; N(C₁₋₄-alkyl)-C(═O)—O—C₁₋₄-alkyl;N(C₁₋₄-alkyl)-C(═O)—NH₂; N(C₁₋₄-alkyl)-C(═O)—N(H)C₁₋₄-alkyl;N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂; N(H)—S(═O)₂—OH;N(H)—S(═O)₂—C₁₋₄-alkyl; N(H)—S(═O)₂—O—C₁₋₄-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)C₁₋₄-alkyl; N(H)—S(═O)₂—N(C₁₋₄-alkyl)₂;N(C₁₋₄-alkyl)-S(═O)₂—OH; N(C₁₋₄-alkyl)-S(═O)₂(C₁₋₄-alkyl);N(C₁₋₄-alkyl)-S(═O)₂—O(C₁₋₄-alkyl); N(C₁₋₄-alkyl)-S(═O)₂—NH₂;N(C₁₋₄-alkyl)-S(═O)₂—N(H)C₁₋₄-alkyl;N(C₁₋₄-alkyl)-S(═O)₂—N(C₁₋₄-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₄-alkyl; S-benzyl; S-aryl; S-heteroaryl; S(═O)—C₁₋₄-alkyl;S(═O)₂—C₁₋₄-alkyl; S(═O)₂-aryl; S(═O)₂-heteroaryl; S(═O)₂—OH;S(═O)₂—OC₁₋₄-alkyl; S(═O)₂O-aryl; S(═O)₂O-heteroaryl; S(═O)₂—NH₂;S(═O)₂—N(H)C₁₋₄-alkyl, S(═O)₂—N(H)-aryl; S(═O)₂—N(H)-heteroaryl andS(═O)₂—N(C₁₋₄-alkyl)₂.

More preferred substituents of “aryl” and “heteroaryl” are selected fromthe group consisting of F; Cl; CF₃; CN; C₁₋₄-alkyl; C(═O)—OH;C(═O)—O—C₁₋₄-alkyl; CO—NH₂; C(═O)—N(H)C₁₋₄-alkyl; C(═O)—N(C₁₋₄-alkyl)₂;OH; O—C₁₋₄-alkyl; O—C(═O)—C₁₋₄-alkyl; OCF₃; OCHF₂; OCH₂F; NH₂;N(H)C₁₋₄-alkyl; N(C₁₋₄-alkyl)₂; N(H)—C(═O)—C₁₋₄-alkyl;N(C₁₋₄-alkyl)-C(═O)C₁₋₄-alkyl; N(H)—S(═O)₂—C₁₋₄-alkyl;N(C₁₋₄-alkyl)-S(═O)₂(C₁₋₄-alkyl); N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)C₁₋₄-alkyl; N(H)—C(═O)—N(C₁₋₄-alkyl)₂;N(C₁₋₄-alkyl)-C(═O)—NH₂; N(C₁₋₄-alkyl)-C(═O)—N(H)C₁₋₄-alkyl;N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂; S(═O)₂C₁₋₄-alkyl; S(═O)₂—NH₂;S(═O)₂—N(H)C₁₋₄-alkyl and S(═O)₂—N(C₁₋₄-alkyl)₂.

The compounds according to the invention are defined by substituents,for example by R^(A), R^(B) and R^(C) (1^(st) generation substituents)which are for their part if appropriate themselves substituted (2^(nd)generation substituents). Depending on the definition, thesesubstituents of the substituents can for their part be resubstituted(3^(rd) generation substituents). If, for example, R^(A)=a C₁₋₄-alkyl(1^(st) generation substituent), then the C₁₋₄-alkyl can for its part besubstituted, for example with a N(H)C₁₋₄-alkyl (2^(nd) generationsubstituent). This produces the functional groupR^(A)=(C₁₋₄-alkyl-N(H)—C₁₋₄-alkyl). The N(H)—C₁₋₄-alkyl can then for itspart be resubstituted, for example with Cl (3^(rd) generationsubstituent). Overall, this produces the functional groupR^(A)=C₁₋₄-alkyl-N(H)—C₁₋₄-alkyl-Cl, wherein the C₁₋₄-alkyl of theN(H)C₁₋₄-alkyl is substituted by Cl.

However, in a preferred embodiment, the 3^(rd) generation substituentsmay not be resubstituted, i.e. there are then no 4^(th) generationsubstituents.

In another preferred embodiment, the 2^(nd) generation substituents maynot be resubstituted, i.e. there are then not even any 3^(rd) generationsubstituents. In other words, in this embodiment, in the case of generalformula (I), for example, the functional groups for R¹ to R³ can each ifappropriate be substituted; however, the respective substituents maythen for their part not be resubstituted.

In some cases, the compounds according to the invention are defined bysubstituents which are or carry a-cycloaliphatic residue or aheterocycloaliphatic residue, respectively, in each case unsubstitutedor mono- or polysubstituted, or which form together with the carbonatom(s) or heteroatom(s) connecting them, as the ring member or as thering members, a ring, for example a cycloaliphatic or aheterocycloaliphatic ring system. Both these cycloaliphatic orheterocycloaliphatic ring systems and the (hetero)cycloaliphatic ringsystems formed in this manner can if appropriate be condensed witha-cycloaliphatic residue, preferably a C₃₋₆-cycloaliphatic residue, orwith a heterocycloaliphatic residue, preferably a 3 to 6 memberedheterocycloaliphatic residue, e.g. with a-cycloaliphatic residue such ascyclohexyl, or a heterocycloaliphatic residue such as morpholinyl,wherein the cycloaliphatic or heterocycloaliphatic residues condensed inthis way can for their part be respectively unsubstituted or mono- orpolysubstituted.

Within the scope of the present invention, the symbol

used in the formulae denotes a link of a corresponding residue to therespective superordinate general structure.

If a residue occurs multiply within a molecule, then this residue canhave respectively different meanings for various substituents: if, forexample, both R^(A) and R^(B) denote a 3 to 6 memberedheterocycloaliphatic residue, then the 3 to 7 memberedheterocycloaliphatic residue can e.g. represent morpholinyl for R^(A)and can represent piperazinyl for R^(B).

In one embodiment of the compound according to the present invention,

R² is selected from the group consisting of H; F; Cl; Br; I; NO₂; CN;CF₃; CF₂H; CFH₂; R¹³; OH; O—R¹³; NH₂; N(H)R¹³; N(R¹³)₂,

wherein R¹³ independently of each other denotes

C₁₋₈-aliphatic residue, unsubstituted or mono- or polysubstituted;

or

C₃₋₆-cycloaliphatic residue or 3 to 7 membered heterocycloaliphaticresidue, in each case unsubstituted or mono- or polysubstituted;

or

C₃₋₆-cycloaliphatic residue or 3 to 7 membered heterocycloaliphaticresidue, in each case unsubstituted or mono- or polysubstituted, and ineach case connected via a C₁₋₄-aliphatic residue, unsubstituted or mono-or polysubstituted.

Preferably, R² is selected from the group consisting of H; F; Cl; Br;CN; CF₃; CF₂H; CFH₂; R¹³; OH; O—R¹³; NH₂; NH—R¹³; N(R¹³)₂,

wherein R¹³ independently of each other denotes

C₁₋₈-aliphatic residue, unsubstituted or mono- or polysubstituted;

or

C₃₋₆-cycloaliphatic residue or 3 to 7 membered heterocycloaliphaticresidue, in each case unsubstituted or mono- or polysubstituted;

or

C₃₋₆-cycloaliphatic residue or 3 to 7 membered heterocycloaliphaticresidue, in each case unsubstituted or mono- or polysubstituted, and ineach case connected via a C₁₋₄-aliphatic residue, unsubstituted or mono-or polysubstituted.

More preferably, R² is selected from the group consisting of H; F; Cl;Br; CN; CF₃; CF₂H; CFH₂; R¹³; OH; O—R¹³; NH₂; NH—R¹³; N(R¹³)₂,

wherein R¹³ independently of each other denotes C₁₋₄-aliphatic residue,unsubstituted or mono- or polysubstituted.

Still more preferably, R² is selected from the group consisting of H; F;Cl, OH, OCH₃, NH₂, N(H)CH₃, N(CH₃)₂, CH₂NH₂, CH₂N(H)CH₃CH₂N(CH₃)₂,CH₂OH; or unsubstituted C₁₋₄-aliphatic residue;

More preferably, R² is selected from the group consisting of H, F, Cl,CH₃; CF₃, CF₂H, CFH₂, CH₂CH₃, CN, OH, CH₂OH, OCH₃, NH₂ and N(H)CH₃.

Even more preferably, R² is selected from the group consisting of C₁,NH₂, CH₃, CH₂OH and CH₂CH₃. Still more preferably, R² is selected fromthe group consisting of H, OH and NH₂. Most preferably, R² denotes H.

In another embodiment of the compound according to the presentinvention,

R¹ denotes H; C₁₋₄-aliphatic residue, unsubstituted or mono- orpolysubstituted; C₃₋₆-cycloaliphatic residue or 3 to 7 memberedheterocycloaliphatic residue, in each case unsubstituted or mono- orpolysubstituted and in each case optionally connected via aC₁₋₄-aliphatic group, which in turn may be unsubstituted or mono- orpolysubstituted; with the proviso that if R¹ represents a 3 to 7membered heterocycloaliphatic residue, said 3 to 7 memberedheterocycloaliphatic residue is connected to the remaining part of thestructure according to general formula (I) via a carbon atom of the 3 to7 membered heterocycloaliphatic residue;

Preferably, R¹ is selected from the group consisting of unsubstitutedC₁₋₄-aliphatic residue or unsubstituted cyclopropyl.

More preferably, is selected from the group consisting of unsubstitutedC₁₋₄-aliphatic residue. Even more preferably, R¹ is selected from CH₃and CH₂CH₃. Most preferably, R¹ denotes CH₃.

According to invention, the compound according to general formula (I) ischaracterized that

n represents 0 or 1,

wherein if n represents 1, then

-   -   K represents C—R⁹ or N or N⁺—O⁻, M represents C—R¹⁰ or N or        N⁺—O⁻, Q represents C—R¹¹ or N or N⁺—O⁻, and R represents C—R¹²        or N or N⁺—O⁻,    -   with the proviso that 0, 1, 2 or 3 of variables K, M, Q and R        independently of one another represent(s) either N or N⁺—O⁻,        whereof 0 or 1 of variables K, M, Q and R independently of one        another represent(s) N⁺—O⁻,        wherein if n represents 0, then    -   K represents C—R⁹ or N or N⁺—O⁻ or O or S or NH or        N(C₁₋₄-aliphatic residue),    -   M represents C—R¹⁰ or N or N⁺—O⁻ or O or S or NH or        N(C₁₋₄-aliphatic residue) and    -   Q represents C—R¹¹ or N or N⁺—O⁻ or O or S or NH or        N(C₁₋₄-aliphatic residue), with the proviso that    -   one of K, M and Q represents O or S or NH or N(C₁₋₄-aliphatic        residue) and the remaining of K, M and Q independently represent        C—R⁹, respectively C—R¹⁰, respectively C—R¹¹ or N or N⁺—O⁻ and        with the proviso that 0, 1 or 2 of variables K, M and Q        independently of one another represent either N or N⁺—O⁻,        whereof 0 or 1 of variables K, M and Q represents N⁺—O⁻.

In another preferred embodiment of the invention, the compound accordingof general formula (I) is selected from the group, consisting offormulae

In particularly preferred embodiment of the invention, the compoundaccording of general formula (I) is selected from the group, consistingof formulae (Ia-1), (Ib-1), (Ic-1), (Id-1), (Ie-1), (If-1), (Ig-1),(Ih-1), (Ii-1), (Ij-1), (Ik-1), (Im-1), (In-1), and (Io-1), wherein eachn represents 1.

More preferably, the compound according of general formula (I) isselected from the group, consisting of formulae (Ia-1), (Ic-1), (Ie-1),(Ig-1), (Ii-1), (Ik-1) and (In-1), wherein each n represents 1.

Even more preferably, the compound according of general formula (I) isselected from the group, consisting of formulae (Ia-1), (Ic-1) and(Ig-1), wherein each n represents 1.

Most preferably, the compound according of general formula (I) isselected from formula (Ia-1), wherein n represents 1.

Within the scope of the present invention, the partial structure

in general formula (I) represents an aryl or a heteroaryl residue. Theresidue is aromatic as depicted by the dashed circle line.

If n represents 1, then the partial structure in general formula (I)represents a 6 membered aryl or heteroaryl residue:

If n represents 0, then the partial structure in general formula (I)represents a 5 membered heteroaryl residue:

Examples for 5 membered heteroaryl residues are thienyl, thiazolyl,isothiazolyl, thiadiazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl,furazanyl, pyrrolyl, pyrazolyl, imidazolyl and triazolyl, in each caseunsubstituted or mono- or polysubstituted.

In a preferred embodiment of the present invention, the compoundaccording to general formula (I) is characterized in that

n represents 1, and

K represents C—R⁹ or N or N⁺—O⁻, M represents C—R¹⁹ or N or N⁺—O⁻, Qrepresents C—R¹¹ or N or N⁺—O⁻, and

R represents C—R¹² or N or N⁺—O⁻,

-   -   with the proviso that 0, 1, 2 or 3 of variables K, M, Q and R        independently of one another represent(s) either N or N⁺—O⁻,        whereof 0 or 1 of variables K, M, Q and R independently        represents N⁺—O⁻.

In another preferred embodiment of the present invention, the compoundaccording to general formula (I) is characterized in that

n represents 1, and

K represents C—R⁹, M represents C—R¹⁰ or N, Q represents C—R¹¹ and Rrepresents C—R¹².

In another preferred embodiment of the present invention, the compoundaccording to general formula (I) is characterized in that

n represents 1, and

K represents C—R⁹, M represents C—R¹⁰, Q represents C—R¹¹ and Rrepresents C—R¹².

In another preferred embodiment of the present invention, the compoundaccording to general formula (I) is characterized in that

n represents 1, and

K represents C—R⁹, M represents N, Q represents C—R¹¹ and R representsC—R¹².

In another preferred embodiment of the present invention, the compoundaccording to general formula (I) is characterized in that

n represents 1, and

K represents C—R⁹, M represents C—R¹⁰, Q represents N and R representsC—R¹².

In another preferred embodiment of the present invention, the compoundaccording to general formula (I) is characterized in that

n represents 1, and

K represents C—R⁹, M represents N, Q represents C—R¹¹ and R representsN.

Within this embodiment of the present invention, a particularsubstitution pattern on the cyclic substituent, incorporating J, K, M, Qand R, proved to be particular beneficial for the activity of thecompounds according to the present invention.

In one preferred embodiment of the invention, the compound according ofgeneral formula (I) is characterized in that

n represents 1, and

R represents C—R¹²,

wherein R¹² is selected from the group consisting of H; CH₃; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; CH₂CH₃; CH₂CF₃; CN; OH; OCH₃; OCHF₂; OCH₂F; OCHF₂;OCF₃; NH₂; NHCH₃; N(CH₃)₂; NH(C═O)CH₃; F; Cl and Br.

Preferably, R⁸ is selected from CH₃; CF₃; CN; OCF₃; F and Cl, even morepreferably from the group consisting of CF₃; CH₃; CN; F and Cl, and mostpreferably R⁸ denotes F.

Preferably, n represents 1, and

R represents C—R¹², wherein R¹² is selected from the group consisting ofH; CH₃; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; CH₂CH₃; CH₂CF₃; CN; OH; OCH₃;OCHF₂; OCH₂F; OCHF₂; OCF₃; NH₂; NHCH₃; N(CH₃)₂; NH(C═O)CH₃; F; Cl andBr, more preferably from the group consisting of H; CH₃; CF₃; CN; OH;OCH₃; F; Cl and Br, and even more preferably from the group consistingof H; CH₃; CN; F and Cl.

In a preferred embodiment of the compound according to the presentinvention, n represents 1, R⁸ denotes F, and R represents N.

In another preferred embodiment of the compound according to the presentinvention, n represents 1, R⁸ denotes F, and R represents C—R¹², whereinR¹² is selected from the group consisting of H; CH₃; CF₃; CN; OH; OCH₃;F and Cl.

In yet another preferred embodiment of the compound according to thepresent invention, n represents 1, R⁸ denotes F, and R represents C—R¹²,wherein R¹² denotes H.

In yet another preferred embodiment of the compound according to thepresent invention, n represents 1, R⁸ denotes F, and R represents C—R¹²,wherein R¹² denotes CH₃.

In yet another preferred embodiment of the compound according to thepresent invention, n represents 1, R⁸ denotes F, and R represents C—R¹²,wherein R¹² denotes CN.

In yet another preferred embodiment of the compound according to thepresent invention, n represents 1, R⁸ denotes F, and R represents C—R¹²,wherein R¹² denotes F.

In yet another preferred embodiment of the compound according to thepresent invention, n represents 1, R⁸ denotes F, and R represents C—R¹²,wherein R¹² denotes Cl.

In one preferred embodiment of the invention, the compound according ofgeneral formula (I) is characterized in that

M represents N or N⁺—O⁻ or C—R¹⁰,

wherein R¹⁰ is selected from the group consisting of H; F; Cl; CN; CF₃;CF₂H; CFH₂; CF₂Cl; CFCl₂; C₁₋₈-aliphatic residue; C(═O)H; C(═O)—NH₂;C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—(C₂₋₄-aliphaticgroup)-OH; O—(C₂₋₄-aliphatic group)-O—C₁₋₈-aliphatic residue;O—C(═O)—C₁₋₈-aliphatic residue; NH₂; N(H)—C₁₋₈-aliphatic residue;NH—(C₂₋₄-aliphatic group)-OH; N(C₁₋₈-aliphatic residue)[(C₂₋₄-aliphaticgroup)-OH]; N(C₁₋₈-aliphatic residue)₂; N(H)—C(═O)—C₁₋₈-aliphaticresidue; N(C₁₋₈-aliphatic residue)-S(═O)₂—C₁₋₈-aliphatic residue;N(H)—S(═O)₂—NH₂ and S(═O)₂—C₁₋₈-aliphatic residue.

Preferably, M represents N or N⁺—O⁻ or C—R¹⁰, wherein R¹⁰ is selectedfrom the group consisting of H; F; Cl; OCH₃; CN; CH₃; CF₃; CF₂H; CFH₂and S(═O)₂—CH₃.

In another preferred embodiment of the invention, the compound accordingof general formula (I) is characterized in that

n represents 1,

R represents C—R¹²,

-   -   wherein R¹² is selected from the group consisting of H; CH₃;        CF₃; CF₂H; CFH₂; CH₂CH₃; CN; OH, OCH₃, OCHF₂, OCH₂F; OCHF₂;        OCF₃; NH₂; NHCH₃; N(CH₃)₂; NH(C═O)CH₃; F and Cl;        K represents C—R⁹ or N and Q represents C—R¹¹ or N,    -   wherein R⁹ and R¹¹ are independently of one another selected        from the group consisting of H; F; Cl; CN; CF₃; CF₂H; CFH₂;        OCF₃; OCF₂H; OCFH₂; an unsubstituted C₁₋₄-aliphatic residue; OH;        and an unsubstituted O—C₁₋₄-aliphatic residue;        and        M represents N or N⁺—O⁻ or C—R¹⁰,    -   wherein R¹⁰ is selected from the group consisting of H; F; Cl;        OCH₃; CN; CH₃; CF₃; CF₂H; CFH₂ and S(═O)₂—CH₃.

In another preferred embodiment of the invention, the compound accordingof general formula (I) is characterized in that

n represents 1,

R represents C—R¹²,

-   -   wherein R¹² is selected from the group consisting of H; CH₃;        CF₃; CF₂H; CFH₂; CH₂CH₃; CN; OH, OCH₃, OCHF₂, OCH₂F; OCHF₂;        OCF₃; NH₂; NHCH₃; N(CH₃)₂; NH(C═O)CH₃; F and Cl;        K represents C—R⁹ and Q represents C—R¹¹,    -   wherein R⁹ and R¹¹ both denote H;        and        M represents N or N⁺—O⁻ or C—R¹⁰,        wherein R¹⁰ is selected from the group consisting of H; F; Cl;        OCH₃; CN; CH₃; CF₃; CF₂H; CFH₂ and S(═O)₂—CH₃.

In another preferred embodiment of the compound according to the presentinvention,

n represents 1,

R⁸ denotes F,

R represents C—R¹², wherein R¹² denotes H,

K represents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ both denoteH, and

M represents N.

In another preferred embodiment of the compound according to the presentinvention,

n represents 1,

R⁸ denotes CH₃,

R represents C—R¹², wherein R¹² denotes H,

K represents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ both denoteH, and

M represents N.

In another preferred embodiment of the compound according to the presentinvention,

n represents 1,

R⁸ denotes F,

R represents C—R¹², wherein R¹² denotes H,

K represents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ both denoteH, and

M represents C—R¹⁰, wherein R¹⁰ denotes H.

In another preferred embodiment of the compound according to the presentinvention,

R⁸ denotes F,

R represents C—R¹², wherein R¹² denotes F,

K represents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ both denoteH, and

M represents N.

In another preferred embodiment of the compound according to the presentinvention,

n represents 1,

R⁸ denotes F,

R represents C—R¹², wherein R¹² denotes F,

K represents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ both denoteH, and

M represents C—R¹⁰, wherein R¹⁰ denotes H.

In another preferred embodiment of the compound according to the presentinvention,

n represents 1,

R⁸ denotes F,

R represents C—R¹², wherein R¹² denotes Cl,

K represents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ both denoteH, and

M represents C—R¹⁰, wherein R¹⁰ denotes H.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that U representsC—R⁴, V represents C—R⁵, W represents C—R⁶, and X represents C—R⁷.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that U representsC—R⁴, V represents C—R⁵, W represents C—R⁶, and X represents N.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that U representsC—R⁴, V represents N, W represents C—R⁶, and X represents N.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that U representsN, V represents C—R⁵, W represents N, and X represents C—R⁷.

In one preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that U representsC—R⁴, V represents N, W represents C—R⁶, and X represents C—R⁷.

In one preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that U representsN, V represents C—R⁵, W represents C—R⁶, and X represents C—R⁷.

In a preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

n represents 1,

K represents C—R⁹ or N or N⁺—O⁻, M represents C—R¹⁰ or N or N⁺—O⁻, Qrepresents C—R¹¹ or N or N⁺—O⁻, and R represents C—R¹² or N or N⁺—O⁻,

-   -   with the proviso that 0, 1, 2 or 3 of variables K, M, Q and R        independently of one another represent(s) either N or N⁺—O⁻,        whereof 0 or 1 of variables K, M, Q and R independently        represents N⁺—O⁻,        U represents C—R⁴, V represents C—R⁵, W represents C—R⁶, and X        represents C—R⁷.

In a preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

n represents 1,

K represents C—R⁹, M represents C—R¹⁰, Q represents C—R¹¹ and Rrepresents C—R¹²,

U represents C—R⁴, V represents C—R⁵, W represents C—R⁶, and Xrepresents C—R⁷.

In a preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

n represents 1,

K represents C—R⁹, M represents N, Q represents C—R¹¹ and R representsC—R¹²,

U represents C—R⁴, V represents C—R⁵, W represents C—R⁶, and Xrepresents C—R⁷.

In another embodiment of the present invention, the compound accordingof general formula (I) is selected from the group, consisting offormulae (Ia-1), (Ic-1), (Ie-1), (Ig-1), (Ii-1), (Ik-1) and (In-1),wherein in each formula U represents C—R⁴, V represents C—R⁵, Wrepresents C—R⁶, and X represents C—R⁷.

In another embodiment of the present invention, the compound accordingof general formula (I) is selected from the group, consisting offormulae (Ia-1), (Ic-1), (Ie-1), (Ig-1), (Ii-1), (Ii-2), (Ik-1) and(In-1), wherein in each formula n represents 1, U represents C—R⁴, Vrepresents C—R⁵, W represents C—R⁶, and X represents C—R⁷.

In another preferred embodiment of the present invention, the compoundaccording of general formula (I) is selected from the group, consistingof formulae (Ia-1), (Ic-1), (Ie-1), (Ig-1), (Ii-1), (Ik-1), and (In-1),wherein in each formula n represents 1,

K represents C—R⁹, M represents C—R¹⁰, Q represents C—R¹¹ and Rrepresents C—R¹²,

U represents C—R⁴, V represents C—R⁵, W represents C—R⁶, and Xrepresents C—R⁷.

In another preferred embodiment of the present invention, the compoundaccording of general formula (I) is selected from the group, consistingof formulae (Ia-1), (Ic-1), (Ie-1), (Ig-1), (Ik-1) and (In-1), whereinin each formula n represents 1,

K represents C—R⁹, M represents N, Q represents C—R¹¹ and R representsC—R¹²,

U represents C—R⁴, V represents C—R⁵, W represents C—R⁶ and X representsC—R⁷.

In another embodiment of the present invention, the compound accordingto the present invention is characterized in that

R⁴, R⁵ and R⁶ independently of each other denote H; F; Cl; CN; CF₃;CF₂H; CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue;C(═O)H; C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphaticresidue; C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphaticresidue)₂; OH; O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂;O—C(═O)—C₁₋₈-aliphatic residue; NH₂; N(H)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)₂; N(H)—O(═O)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂or S(═O)₂—C₁₋₈-aliphatic residue.

In a preferred embodiment of the compound according to the presentinvention, R⁴, R⁵ and R⁶ independently of each other denotes H; F; Cl;OCH₃; OCHF₂; OCFH₂; OCF₃; CN; CH₃; CF₃; CF₂H or CFH₂.

In one particular preferred embodiment of the compound according to thepresent invention, R⁵ denotes H; F; Cl; OCH₃; OCHF₂; OCFH₂; OCF₃; CN;CH₃; CF₃; CF₂H or CFH₂.

In another particular preferred embodiment of the compound according tothe present invention, R⁴ denotes H; F; Cl; OCH₃; OCHF₂; OCFH₂; OCF₃;CN; CH₃; CF₃; CF₂H or CFH₂.

In another particular preferred embodiment of the compound according tothe present invention, R⁶ denotes H; F; Cl; OCH₃; OCHF₂; OCFH₂; OCF₃;CN; CH₃; CF₃; CF₂H or CFH₂.

In another embodiment of the present invention, the compound accordingto the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—O(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residue.

In preferred embodiment of the present invention, the compound accordingto the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;OCF₃; OCF₂H; OCFH₂; cyclopropyl; unsubstituted C₁₋₄-aliphatic residue;OH and unsubstituted O—C₁₋₄-aliphatic residue.

In a particularly preferred embodiment of the present invention, thecompound according to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—O(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residueandX represents C—R⁷ andR⁷ represents H or F or CH₃ or CF₃.

In a particularly preferred embodiment of the present invention, thecompound according to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;OCF₃; OCF₂H; OCFH₂; cyclopropyl; unsubstituted C₁₋₄-aliphatic residue;OH and unsubstituted O—C₁₋₄-aliphatic residue; and

X represents C—R⁷ and

R⁷ represents H or F or CH₃ or CF₃.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—O(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residueandU represents C—R⁴ or N, V represents C—R⁵ or N, W represents C—R⁶ or N,whereinR⁴, R⁵ and R⁶ are independently selected from the group consisting of H;F; Cl; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃;C₁₋₈-aliphatic residue; C(═O)H; C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue;C(═O)O—C₁₋₈-aliphatic residue; C(═O)NH—C₁₋₈-aliphatic residue;C(═O)N(C₁₋₈-aliphatic residue)₂; OH; O—C₁₋₈-aliphatic residue; OCF₃;OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphatic residue; NH₂; N(H)—C₁₋₈-aliphaticresidue; N(C₁₋₈-aliphatic residue)₂; N(H)—O(═O)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)-S(═O)₂—C₁₋₈-aliphatic residue;N(H)—S(═O)₂—NH₂; S(═O)₂—C₁₋₈-aliphatic residueandX represents C—R⁷, whereinR⁷ represents H or F or CH₃ or CF₃.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residueandV represents C—R⁵, whereinR⁵ is selected from the group consisting of H; F; Cl; CN; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—O(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residueandX represents C—R⁷, whereinR⁷ represents H or F or CH₃ or CF₃.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residueandV represents C—R⁵, whereinR⁵ is selected from the group consisting of H; F; Cl; CN; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—O(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residueandU represents C—R⁴, W represents C—R⁶ and X represents C—R⁷, whereineach of R⁴, R⁶ and R⁷ represents H.

In another particularly preferred embodiment of the present invention,the compound according to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;OCF₃; OCF₂H; OCFH₂; cyclopropyl; unsubstituted C₁₋₄-aliphatic residue;OH and unsubstituted O—C₁₋₄-aliphatic residue and

V represents C—R⁵, wherein R⁵ is selected from the group consisting ofH; F; Cl; OCH₃; OCHF₂; OCFH₂; OCF₃; CN; CH₃; CF₃; CF₂H or CFH₂,

and

U represents C—R⁴, W represents C—R⁶ and X represents C—R⁷, wherein eachof R⁴, R⁶ and R⁷ represents H.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—O(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residueandW represents C—R⁶, whereinR⁶ is selected from the group consisting ofH; F; Cl; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃;C₁₋₈-aliphatic residue; C(═O)H; C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue;C(═O)O—C₁₋₈-aliphatic residue; C(═O)NH—C₁₋₈-aliphatic residue;C(═O)N(C₁₋₈-aliphatic residue)₂; OH; O—C₁₋₈-aliphatic residue; OCF₃;OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphatic residue; NH₂; N(H)—C₁₋₈-aliphaticresidue; N(C₁₋₈-aliphatic residue)₂; N(H)—O(═O)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)-S(═O)₂—C₁₋₈-aliphatic residue;N(H)—S(═O)₂—NH₂; S(═O)₂—C₁₋₈-aliphatic residueandX represents C—R⁷, whereinR⁷ represents H.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residueandW represents C—R⁶, whereinR⁶ is selected from the group consisting of H; F; Cl; CN; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residueandU represents C—R⁴, V represents C—R⁵ and X represents C—R⁷, whereineach of R⁴, R⁵ and R⁷ represents H.

In another preferred embodiment of the present invention, the compoundaccording to the present invention is characterized in that

R³ is cyclopropyl

and

W represents C—R⁶, wherein

R⁶ is selected from the group consisting of H; F; Cl; CN; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)H;C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residueandU represents C—R⁴, V represents C—R⁵ and X represents C—R⁷, whereineach of R⁴, R⁵ and R⁷ represents H.

In another particularly preferred embodiment of the present invention,the compound according to the present invention is characterized in that

R³ is selected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂;OCF₃; OCF₂H; OCFH₂; cyclopropyl; unsubstituted C₁₋₄-aliphatic residue;OH and unsubstituted O—C₁₋₄-aliphatic residue and

W represents C—R⁶, wherein R⁶ is selected from the group consisting ofO—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂;

and

U represents C—R⁴, W represents C—R⁶ and X represents C—R⁷, wherein eachof R⁴, R⁶ and R⁷ represents H.

In another particularly preferred embodiment of the present invention,the compound according to the present invention is characterized in that

R³ is cyclopropyl and

W represents C—R⁶, wherein R⁶ is selected from the group consisting ofO—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂;

and

U represents C—R⁴, W represents C—R⁶ and X represents C—R⁷, wherein eachof R⁴, R⁶ and R⁷ represents H.

In a particular preferred embodiment of the present invention, thecompound according to the present invention is characterized in that

-   R¹ denotes an unsubstituted C₁₋₄-aliphatic residue, preferably    denotes CH₃ or CH₂CH₃; more preferably CH₃;-   R² denotes H; F; Cl, OH, OCH₃, NH₂, NHCH₃, N(CH₃)₂, CH₂NH₂,    CH₂N(H)CH₃CH₂N(CH₃)₂, CH₂OH or unsubstituted C₁₋₄-aliphatic residue;    preferably denotes H, Cl, NH₂, CH₃, CH₂OH and CH₂CH₃; more    preferably H;-   U represents C—R⁴ or N, V represents C—R⁵ or N, W represents C—R⁶ or    N, and X represents C—R⁷, with the proviso that 0, 1, 2 or 3 of    variables U, V, W and X independently of one another represent(s) N,    -   and with the proviso that at least one of U, V and W does not        represent N,-   R³ denotes F; Cl; CN; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂;    cyclopropyl; unsubstituted C₁₋₄-aliphatic residue; OH or    unsubstituted O—C₁₋₄-aliphatic residue;-   R⁷ denotes H, F, CH₃ or CF₃; and-   R⁴, R⁵ and R⁶ are independently selected from the group consisting    of H; F; Cl; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃;    C₁₋₈-aliphatic residue; C(═O)H; C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic    residue; C(═O)O—C₁₋₈-aliphatic residue; C(═O)NH—C₁₋₈-aliphatic    residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH; O—C₁₋₈-aliphatic    residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphatic residue; NH₂;    N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;    N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic    residue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;    S(═O)₂—C₁₋₈-aliphatic residue;-   n represents 1,-   R⁸ is selected from the group consisting of F, Cl, CF₃, CF₂H, CFH₂,    CH₃, CN, OCH₃, OCF₂H, OCFH₂, and OCF₃;-   K represents C—R⁹ and Q represents C—R¹¹,    -   wherein R⁹ and R¹¹ are independently of one another selected        from the group consisting of H; F; Cl; CN; CF₃; CF₂H; CFH₂;        OCF₃; OCF₂H; OCFH₂; CH₃; OH; and OCH₃; and-   M represents N or N⁺—O⁻ or C—R¹⁰,    -   wherein R¹⁰ is selected from the group consisting of H; F; Cl;        OCH₃; CN; CH₃; CF₃; CF₂H; CFH₂ or S(═O)₂—CH₃,-   R represents C—R¹²,    -   wherein R¹² is selected from the group consisting of H; CH₃;        CF₃; CF₂H; CFH₂; CH₂CH₃; CN; OH; OCH₃; OCHF₂; OCH₂F; OCHF₂;        OCF₃; F and Cl;        optionally in the form of a single stereoisomer or a mixture of        stereoisomers, in the form of the free compound and/or a        physiologically acceptable salt and/or a physiologically        acceptable solvate thereof.

In a particular preferred embodiment of the present invention, thecompound according to the present invention is characterized in that thecompound has general formula (Ia),

whereinR¹, R², K, M, Q, R, n, U, V, W and X are defined as before andR⁸ denotes F, Cl, CN, CF₃, CF₂H, CFH₂, CH₃ or OCH₃.

In a particular preferred embodiment of the present invention, thecompound according to the present invention is characterized in that thecompound has general formula (Iaa),

-   -   wherein    -   R¹, R², U, V, W and X are defined as before,    -   R⁸ denotes F, Cl, CN, CF₃, CF₂H, CFH₂, CH₃ or O—CH₃    -   and    -   K, M, Q and R independently represent N, CH or C—R^(8a),    -   wherein R^(8a) denotes F, Cl, CN, CF₃, CF₂H, CFH₂, CH₃, CH₂CH₃,        O—CH₃ or O—CH₂CH₃, with the proviso, that 0 or 1 of the        substituents K, M, Q and R represent N.

In a particular preferred embodiment of the present invention, thecompound according to the present invention is selected from the group,consisting of

-   1    N-(2,6-Difluoro-phenyl)-5-(2-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   2    N-(2,4-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   3    5-(2-Ethoxy-5-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   4    N-(2,6-Difluoro-phenyl)-5-(2-ethoxy-5-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   5-(2,5-Difluoro-phenyl)-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   6    N-(2,6-Difluoro-phenyl)-5-[2-fluoro-5-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   7    N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylic    acid amide;-   8    N-(2,6-Difluoro-phenyl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   9    N-(3-Fluoro-pyridin-4-yl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   10    N-(2,6-Difluoro-phenyl)-5-(5-fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   11    5-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   12    5-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   13    5-(2,5-Dimethoxyphenyl)-N-(2-fluoro-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   14    5-(2,5-Dimethoxyphenyl)-1-methyl-N-[3-(trifluoromethyl)-pyridin-4-yl]-1H-pyrazole-3-carboxylic    acid amide;-   15    N-(3-Cyano-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   16    5-(2,5-Dimethoxyphenyl)-1-methyl-N-(4-methyl-pyridin-3-yl)-1H-pyrazole-3-carboxylic    acid amide;-   17    5-(2,5-Dimethoxyphenyl)-N-(4,6-dimethyl-pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   18 5-(2,5-Di    methoxyphenyl)-1-methyl-N-(5-methyl-pyrimidin-4-yl)-1H-pyrazole-3-carboxylic    acid amide;-   19    5-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   20    5-(2,5-Dimethoxyphenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1H-pyrazole-3-carboxylic    acid amide;-   21    N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   22    5-(5-Chloro-2-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   23    5-(5-Chloro-2-methyl-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   24    N-(3-Fluoro-pyridin-4-yl)-5-(4-methoxy-2-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   25    5-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1,4-dimethyl-1H-pyrazole-3-carboxylic    acid amide;-   26    5-(5-Chloro-2-methyl-phenyl)-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   27    5-(2,5-Dimethoxyphenyl)-1-methyl-N-(o-tolyl)-1H-pyrazole-3-carboxylic    acid amide;-   28    5-(5-Chloro-2-methyl-phenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1H-pyrazole-3-carboxylic    acid amide;-   29    N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylic    acid amide;-   30    N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylic    acid amide;-   31    N-(2,6-Difluoro-4-methoxy-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   32    5-(2,5-Dimethoxyphenyl)-N-(2-fluoro-6-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   33    5-(2,5-Dimethoxyphenyl)-N-(2-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   34    N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   35    N-(2-Chloro-6-fluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   36    5-[2-Chloro-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   37    N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-ethyl-1H-pyrazole-3-carboxylic    acid amide;-   38    5-[2-Cyano-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   39    4-Chloro-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   40    4-Chloro-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   41    N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1H-pyrazole-3-carboxylic    acid amide;-   42    N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-ethyl-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   43    N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   44    4-Amino-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   45    5-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   46    5-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(3,5-difluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   47    5-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   48 4-Amino-5-(2,5-di    methoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   49    N-(3,5-Difluoro-pyridin-4-yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   50 N,5-Bis(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   51    N-(2,6-Difluoro-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   52    N-(2-Chloro-6-methyl-phenyl)-5-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   53    5-(2,6-Difluoro-phenyl)-N-(3-fluoro-5-methyl-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   54    5-[2-Fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-N-[2-(trifluoromethyloxy)-phenyl]-1H-pyrazole-3-carboxylic    acid amide;-   55    N-(2,4-Difluoro-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   56    N-(2-Cyano-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   57    N-(2,4-Dichlorophenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   58    N-(2,6-Difluoro-4-methoxy-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   59    N-(2-Fluoro-6-methyl-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   60    5-[2-Fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-N-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylic    acid amide;-   61    N-(2-Fluorophenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   62    N-(3-Fluoro-pyridin-4-yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   63    N-(3-Fluoro-5-methyl-pyridin-4-yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   64    1-Methyl-5-(4-methyl-pyridin-3-yl)-N-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylic    acid amide;-   65    N-(3-Fluoro-5-methyl-pyridin-4-yl)-1-methyl-5-(4-methyl-pyridin-3-yl)-1H-pyrazole-3-carboxylic    acid amide;-   66    N-(2,6-Difluoro-phenyl)-5-(2-methoxy-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylic    acid amide;-   67    N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-4-methylamino-1H-pyrazole-3-carboxylic    acid amide;    optionally in the form of the free compound and/or a physiologically    acceptable salt thereof and/or a physiologically acceptable solvate    thereof.

The compounds according to the present invention are useful for calciumrelease-activated calcium (CRAC) channel regulation, preferably for usein CRAC channel inhibition.

The substances according to the invention hence act, for example, on theCRAC channel relevant in connection with various diseases, so that theyare suitable as a pharmacologically active compound in pharmaceuticalcompositions.

The compounds according to the first aspect of the present invention andthe corresponding stereoisomers and the respective salts and solvatesare toxicologically safe and are therefore suitable as pharmacologicallyactive ingredients in pharmaceutical compositions.

In another aspect of the present invention, the invention therefore alsoprovides pharmaceutical compositions, containing at least one compoundaccording to the invention and optionally one or more suitable,pharmaceutically compatible auxiliaries and/or, if appropriate, one ormore further pharmacologically active compounds.

The pharmaceutical composition according to the invention is suitablefor administration to adults and children, including toddlers andbabies.

The pharmaceutical composition according to the invention may be foundas a liquid, semisolid or solid pharmaceutical form, for example in theform of injection solutions, drops, juices, syrups, sprays, suspensions,tablets, patches, capsules, plasters, suppositories, ointments, creams,lotions, gels, emulsions, aerosols or in multiparticulate form, forexample in the form of pellets or granules, if appropriate pressed intotablets, decanted in capsules or suspended in a liquid, and also beadministered as much.

In addition to at least one compound according to the invention, ifappropriate in the form of one of its pure stereoisomers, in particularenantiomers or diastereomers, its racemate or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany desired mixing ratio, or if appropriate in the form of acorresponding salt or respectively in the form of a correspondingsolvate, the pharmaceutical composition according to the inventionconventionally contains further physiologically compatiblepharmaceutical auxiliaries which can for example be selected from thegroup consisting of excipients, fillers, solvents, diluents,surface-active substances, dyes, preservatives, blasting agents, slipadditives, lubricants, aromas and binders. Likewise the compoundaccording to the invention, if appropriate in the form of one of itspure stereoisomers, or if appropriate in the form of a correspondingsalt or respectively in the form of a corresponding solvate, may alsoincorporated into the pharmaceutical composition in the form of aprodrug, which releases the active pharmacological agent through normalmetabolic processes.

The selection of the physiologically compatible auxiliaries and also theamounts thereof to be used depend on whether the pharmaceuticalcomposition is to be applied orally, subcutaneously, parenterally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally, buccally, rectally or locally, for example to infectionsof the skin, the mucous membranes and of the eyes. Preparations in theform of tablets, dragées, capsules, granules, pellets, drops, juices andsyrups are preferably suitable for oral application; solutions,suspensions, easily reconstitutable dry preparations and also sprays arepreferably suitable for parenteral, topical and inhalative application.The compounds according to the invention used in the pharmaceuticalcomposition according to the invention in a repository in dissolved formor in a plaster, agents promoting skin penetration being added ifappropriate, are suitable percutaneous application preparations. Orallyor percutaneously applicable preparation forms can release therespective compound according to the invention also in a delayed manner.

The pharmaceutical compositions according to the invention are preparedwith the aid of conventional means, devices, methods and process knownin the art, such as are described for example in “Remington'sPharmaceutical Sciences”, A. R. Gennaro (Editor), 17^(th) edition, MackPublishing Company, Easton, Pa., 1985, in particular in Part 8, Chapters76 to 93. The corresponding description is introduced herewith by way ofreference and forms part of the disclosure. The amount to beadministered to the patient of the respective substituted compoundsaccording to the invention of the above-indicated general formula I mayvary and is for example dependent on the patient's weight or age andalso on the type of application, the indication and the severity of thedisorder. Conventionally 0.001 to 100 mg/kg, preferably 0.05 to 75mg/kg, particularly preferably 0.05 to 50 mg of at least one suchcompound according to the invention are applied per kg of the patient'sbody weight.

CRAC channels are believed to be involved in a variety of diseases ordisorders in mammals such as humans. These include inflammatorydisorders, allergic disorders and disorders of the immune system as wellas disorders involving platelet or thrombotic activity.

Examples of allergic disorders include: rhinitis (such as allergicrhinitis), sinusitis, rhinosinusitis, chronic or recurrent otitis media,drug reactions, insect sting reactions, latex allergy, conjunctivitis,urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitisand food allergies.

Examples of inflammatory disorders include: inflammatory lung disorders(such as asthma, acute respiratory distress syndrome, acute lung injury,chronic obstructive pulmonary disease, bronchiectasis and cysticfibrosis); chronic inflammatory disorders of joints (such as arthritis,rheumatoid arthritis, osteoarthritis and bone diseases associated withincreased bone resorption); inflammatory bowel diseases (such asBarrett's oesophagus, ileitis, ulcerative colitis and Crohn's disease);inflammatory disorders of the eye (such as corneal dystrophy, trachoma,uveitis, sympathetic ophthalmitis and endophthalmitis); inflammatorydiseases of the kidney (such as glomerulonephritis, nephrosis, nephriticsyndrome and IgA nephropathy); inflammatory diseases of the liver;inflammatory disorders of the skin (such as psoriasis and eczema);inflammatory diseases of the central nervous system (such as chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimers disease, infectiousmeningitis, enceophalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis); inflammatory diseases of the muscle (such as polymyositisand polymyalgia rheumatica); inflammatory diseases of the heart (such asmyocarditis and cardiomyopathy, ischemic heart disease, myocardialinfarction and atherosclerosis); other diseases with significantinflammatory components, including tuberculosis; leprosy; allogeneic orxenogeneic transplantation (cells, stem cells, tissues or organs) graftrejection, graft-versus-host disease; pre-eclampsia; endometriosis,chronic liver failure; brain and spinal cord trauma and cancer; andconditions where systemic inflammation of the body may also be present(such as septic shock, hemorrhagic or anaphylactic shock or shockinduced by cancer chemotherapy).

Examples of disorders of the immune system include: autoimmune diseasesof the central and peripheral nervous system (such as multiplesclerosis, myasthenia gravis, Eaton-Lambert Myasthenic syndrome);autoimmune neurophathies (such as Guillain-Barré); autoimmune diseasesof the eye (such as autoimmune uveitis); autoimmune diseases of theblood (such as autoimmune haemolytic anemia, pernicious anemia, andautoimmune thrombocytopenia e.g. Idiopathic Thrombocytopaenic Purpura);autoimmune diseases of the vasculature (such as temporal arteritis,anti-phospholipid syndrome, vasculitides e.g. Wegener's granulomatosisand Behcet's disease); autoimmune diseases of the skin (such as alopeciaareata, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, bullouspemphigoid and vitiligo); autoimmune disease of the gastrointestinaltract (such as coeliac disease, Crohn's disease, ulcerative colitis,primary biliary cirrhosis and autoimmune hepatitis); autoimmunedisorders of the endocrine glands (such as Type 1 diabetes mellitus,autoimmune thyroiditis, Grave's disease, Hashimoto's thyroiditis,autoimmune oophoritis and orchitis); autoimmune disorder of the adrenalgland (such as Addisons disease); autoimmune disorders of the exocrineglands (such as Sjogren's syndrome); and multi system autoimmunediseases including connective tissue and musculoskeletal system diseases(such as rheumatoid arthritis, systemic lupus erythematosus,scleroderma, polymyositis, dermatomyositis), spondyloarthropathies (suchas ankylosing spondylitis and psoriatic arthritis).

Examples of conditions where anti-platelet or anti-thrombotic activityis useful for treatment and/or prophylaxis include: ischemic heartdisease, myocardial infarction, cerebrovascular accident (stroke) andvascular thrombosis (venous, arterial and intra-cardiac).

Further diseases or conditions which may be treated by the compounds ofthe invention include conditions where mast cells and basophilscontribute to pathology, such as mast cell leukaemia, mastocytosis,endometriosis and basophil leukaemia.

The term “disorders and/or diseases which are mediated, at least inpart, by CRAC channels”, is intended to include each of or all of theabove disease states.

It is believed that the compounds of formula (I), having ICRACinhibitory activity, may inhibit mast cell degranulation and/or inhibitT cell activation. Compounds having such activity may be particularlysuitable for the treatment of a number of diseases and conditions, forexample asthma; allergies such as allergic rhinitis; and nasalpolyposis.

Due to the key role of calcium in the regulation of cellularproliferation in general, calcium channel inhibitors could act ascytostatic agents which may be useful in the treatment of diseases ofabnormal cellular proliferation, e.g. benign prostatic hyperplasia orfamilial adenomatosis polyposis. The compounds may be useful for thetreatment of a variety of cancers as hematopoietic tumors of lymphoidlineage (such as leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma and Hodgkin'slymphoma); hematopoietic tumors of myeloid lineage (such as acute andchronic myelgenous leukemias); carcinomas, tumors of mesenchymal origin;tumors of the central and peripheral nervous system (such as astrocytomaand neuroblastoma) and other tumors such as melanoma and sarcoma.

Another aspect of the present invention therefore relates to a compoundaccording to the first aspect of the present invention for the treatmentand/or prophylaxis of a or more disorder and/or disease, selected fromthe group consisting of glomerulonephritis, uveitis, hepatic diseases ordisorders, especially hepatitis, renal diseases or disorders, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis (RA),multiple sclerosis, inflammatory bowel disease (IBD), especiallyBarrett's oesophagus, ileitis, ulcerative colitis or Crohn's Disease,vasculitis, dermatitis, dermatomyositis, atopic dermatitis, scleroderma,osteoarthritis, inflammatory muscle disease, allergic rhinitis,vaginitis, interstitial cystitis, osteoporosis, eczema, psoriasis,allogeneic or xenogeneic transplantation (cells, stem cells, tissues ororgans) graft rejection, graft-versus-host disease, lupus erythematosus,type I diabetes, pulmonary fibrosis, thyroiditis, myasthenia gravis,autoimmune hemolytic anemia, cystic fibrosis, chronic relapsinghepatitis, hepatitis, primary biliary cirrhosis, allergicconjunctivitis, asthma, nasal polyposis; Sjogren's syndrome, cancer andother proliferative diseases, and autoimmune diseases or disorders.

Another embodiment of this aspect of the present invention relates to acompound according to the first aspect of the present invention for thetreatment and/or prophylaxis of autoimmune diseases, in particularrheumatoid arthritis and psoriatic arthritis.

Another embodiment of this aspect of the present invention relates to acompound according to the first aspect of the present invention for thetreatment and/or prophylaxis of inflammatory disorders of the skin, inparticular psoriasis as and/or eczema, most preferably psoriasis.

Another embodiment of this aspect of the present invention relates to acompound according to the first aspect of the present invention for thetreatment and/or prophylaxis of chronic inflammatory disorders of thejoints, in particular arthritis, rheumatoid arthritis and/orosteoarthritis arthritis, most preferably rheumatoid arthritis (RA).

Yet another embodiment of this aspect of the present invention relatesto a compound according to the first aspect of the present invention forthe treatment and/or prophylaxis of inflammatory bowel diseases, inparticular Barrett's oesophagus, ileitis, ulcerative colitis and Crohn'sdisease.

Yet another embodiment of this aspect of the present invention relatesto a compound according to the first aspect of the present invention forthe treatment and/or prophylaxis of allogeneic or xenogeneictransplantation graft rejection, in particular transplantation grafts ofcells, stem cells, tissues and/or organs.

Yet another embodiment of this aspect of the present invention relatesto a compound according to the first aspect of the present invention forthe treatment and/or prophylaxis of autoimmune diseases of the centraland peripheral nervous system, in particular multiple sclerosis,myasthenia gravis and/or Eaton-Lambert Myasthenic syndrome, mostpreferably multiple sclerosis.

Yet another embodiment of this aspect of the present invention relatesto a compound according to the first aspect of the present invention forthe treatment and/or prophylaxis of inflammatory lung disorders, inparticular asthma, acute respiratory distress syndrome, acute lunginjury, chronic obstructive pulmonary disease, bronchiectasis and/orcystic fibrosis, most preferably asthma.

Yet another embodiment of this aspect of the present invention relatesto a compound according to the first aspect of the present invention forthe treatment and/or prophylaxis of allergies, in particular allergicrhinitis.

Another aspect of the present invention provides the use of at least onecompound according to the present invention for the preparation of apharmaceutical composition for the treatment and/or prophylaxis of oneor more of the above mentioned diseases and/or disorders.

One embodiment of the invention provides the use of at least onecompound according to the present invention for the preparation of apharmaceutical composition for the treatment and/or prophylaxis of oneor more of the diseases and/or disorders, selected from the groupconsisting of inflammatory disorders and/or autoimmune diseases and/orallergic disorders, preferably selected from the group consisting ofpsoriasis and/or psoriatic arthritis; rheumatoid arthritis; inflammatorybowel disease; asthma and allergic rhinitis.

Another aspect of the present invention is a method for the treatmentand/or prophylaxis, in particular for of one or more of the abovementioned diseases and/or disorders,

in a mammal, in particular in a human, in need of treatment and/orprophylaxis of the respective disease and/or disorder,

which comprises the administration of an effective amount of at leastone compound according the present invention or the administration of apharmaceutical composition according to the invention to the mammal.

One embodiment of the invention is a method for the treatment and/orprophylaxis of disorders and/or diseases, selected from the groupconsisting of inflammatory disorders and/or autoimmune diseases and/orallergic disorders, preferably selected from the group consisting ofpsoriasis and/or psoriatic arthritis; rheumatoid arthritis; inflammatorybowel disease; asthma and allergic rhinitis,

in a mammal, in particular in a human, in need of treatment and/orprophylaxis of the respective disease and/or disorder,

which comprises the administration of an effective amount of at leastone compound according the present invention or the administration of apharmaceutical composition according to the invention to the mammal.

The term “effective amount” according to the present invention meansthat administered amount of the compound or the pharmaceuticalcomposition that will result in a therapeutically desired biological ormedical response of a tissue, system, mammal or human.

A therapeutically desired biological or medical response is understoodto be an improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder in a mammal, as compared to acorresponding mammal who has not been administered such amount. The term“therapeutically desired biological or medical response” includes alsothe enhancement of a normal physiological function.

The term “compounds according to the first aspect of the presentinvention” in foregoing aspects of the invention encompasses allpossible stereoisomers and tautomers as well as the respectivecorresponding acids, bases, salts and solvates.

The embodiments and in particular the preferred embodiments of anyaspect of the present invention apply to all other aspects of theinventions respectively.

Compounds of the invention may be made by the methods depicted in thereaction schemes below and described for examples of the invention. Thefollowing reaction schemes are illustrative only and variousmodifications of the methods may be made by those skilled in the art inorder to obtain compounds of the invention.

Condensation of an appropriate aryl alkyl ketone with a glyoxalatediester as diethyl glyoxalate yields a β-ketone intermediate thatreadily cyclises upon treatment with a suitably substituted hydrazine toafford the aryl pyrazole ethyl ester as a mixture of isomers. Afterseparation of the isomers, for instance by flash chromatography,transformation of the ester into compounds of the invention can beperformed via saponification and amide coupling by one of the variousmethods known to those skilled in the art or a conventional one stepmethod (Scheme 1). Alternatively, as shown in Scheme 1a cyclisation ofthe β-ketone intermediate can be performed with unsubstituted hydrazine.Alkylation with suitable halogenides or equivalents again leads tosubstituted aryl pyrazole ethyl ester derivatives. Separation of isomersand subsequent steps follow the route depicted in Scheme 1.

Substitutions R₂≠H may be introduced on stage of the ketone startingmaterial (as shown in Scheme 1, e.g. R₂═CH₃), the β-ketone intermediateor the aryl pyrazole ester (e.g. R₂═C₁, NO₂ as shown in Scheme 1b) or atany other suitable stage of the synthesis optionally followed by furthermodifications (e.g. reduction of NO₂ to NH₂ with an appropriate reagenton this or later stage). Subsequent steps may then follow the routedepicted in Scheme 1. In particular cases a protecting group may beemployed.

As shown in Scheme 2 and 3 alternatively Pd-catalyzed coupling methodsmay be used to obtain compounds of the invention. Scheme 2 illustratesthe synthesis via a pyrazole bromide or triflate employed in a Suzukicross coupling with an appropriate boronic acid or ester. The couplingmay also be performed on a pyrazole ester intermediate. Scheme 3provides an example how a 5-unsubstituted pyrazole ester is convertedinto a boronic ester in the presence of an iridium catalyst andbispinacolatodiborane. Suzuki coupling with an appropriate arylhalogenide or triflate subsequently gives aryl pyrazole esters that canbe converted to compounds of the invention as shown in Scheme 1. Adirect coupling of the 5-unsubstituted pyrazole with an aryl halogenidemay provide an alternative synthesis strategy for aryl pyrazole esterformation.

In general, further modifications may be performed on aryl pyrazoleamides or esters readily assembled according to the synthesis schemesprovided above. For instance a halogen substitution, preferably Br or I,in the position U, V, W or X may be transformed by a Pd catalyzedcoupling as Suzuki, Stille and Negishi, or alternatively undergo aBuchwald coupling to afford compounds of the invention or their esterintermediates (Scheme 4). Other examples include the use of ancarboxylic acid, ester or nitrile for further modifications and othersynthesis transformation known to those skilled in the art.

Exemplified Compounds

The following examples of the invention were prepared according toreaction schemes 1 to 4.

Starting materials and reagents are available from commercial supplierssuch as for example Acros, Aldrich, Apollo, Fluka, FluoroChem,Lancaster, Manchester Organics, MatrixScientific, Maybridge, Merck, TCI,Oakwood, etc., or the synthesis has been described as such in theliterature or the materials may be prepared by conventional methodsknown to those skilled in the art.

All the intermediate products and exemplary compounds were analyticallycharacterized by means of ¹H-NMR spectroscopy. In addition, massspectrometry tests (MS, m/z for [M+H]⁺) were carried out for all theexemplary compounds and selected intermediate products.

ABBREVIATIONS

The indication “equivalents” (“eq.” or “eq” or “equiv.”) means molarequivalents, “RT” or “rt” means room temperature (23±7° C.), “M” areindications of concentration in mol/l, “aq.” means aqueous, “sat.” meanssaturated, “sol.” means solution, “conc.” means concentrated.

Further Abbreviations

-   Cy cyclohexane-   DMF N,N-dimethylformamide-   EDC.HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   Et₂O diethyl ether-   EtOH ethanol-   EtOAc ethyl acetate-   h hour(s)-   HATU    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HOBT 1-hydroxybenzotriazole-   MeOH methanol-   min minute(s)-   PEPPSI™-Ipr    [1,3-bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)    dichloride-   Pd(dppf)Cl₂.CH₂Cl_(2 [)1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),    complex with dichloromethane-   THF tetrahydrofuran    Analytical and Purification Methods:    Liquid Chromatography with Mass Spectrometry Detection: LC-MS    Method 1:    Agilent LC-MS 1200 Rapid Resolution with detector MSD6140    Detection: MM-ES+APCI+DAD (254 nm)    Fragmentation: 50 V [pos/neg]    Column: Agilent SB-C18, 2.1×30 mm, 3.5 micron    Column temperature: 30° C.    Flow rate: 0.8 mL/min.    Runtime: 4 min.    Eluent: A: Water; B: methanol with 1 vol-% formic acid    Gradient:    -   t=0 min.: 95/5 (A/B)    -   t=1.00 min.: 95/5 (A/B)    -   t=4.00 min.: 0/100 (A/B)        Method 2:        Agilent 1290 Infinity UHPLC-TOF system        Detection: Agilent G4212A DAD (190-400 nm)+Agilent 6224 TOF        Column: Zorbax SB-C18 Rapid Resolution HD, 2.1×50 mm        Column temperature: 80° C.        Flow rate: 2.3 mL/min        Runtime: 1.38 min.        Eluent: A: Water with 0.1 vol-% formic acid; B: acetonitrile        with 0.1 vol-% formic acid        Gradient:    -   t=0 min.: 98/2 (A/B)    -   t=1.20 min.: 0/100 (A/B)    -   t=1.29 min.: 0/100 (A/B)    -   t=1.31 min.: 98/2 (A/B)    -   t=1.39 min.: 98/2 (A/B)        Chromatography        Büchi MPLC system (Stationary phase: silica gel, 40-50μ)        PuriFlash 430 (Stationary phase: Interchim®-cartridges)        Preparative HPLC        Coupled LC-MS Agilent 1200/1260 Autopurification system        Column: Machery-Nagel Nucelodur ISIS C18 VP, 21×100 mm        Flow rate: 35 mL/min.        Runtime: 12 min.        Eluent: A: Water; B: methanol        Gradient: 30-100% B

Synthesis of Compounds According to Present Invention Synthesis Example1N-(2,6-Difluoro-phenyl)-5-(2-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

A solution of 5-(2-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic acid(0.400 g) in SOCl₂ (3 mL) was heated to 60° C. for 1 h. The mixture waschilled and the volatiles were removed under reduced pressure. Theresidue was redissolved in CH₂Cl₂ (13 mL) and NEt₃ (219 μL) and2,6-difluoroaniline (113 μL) were consecutively added. The mixture wasstirred at ambient temperature for 16 h and was washed with sat. NH₄Cl.The organic layer was dried and the volatiles were removed under reducedpressure. The residue was purified by chromatography (Interchim®cartridge 50SiHP/12 g, CH₂Cl₂/MeOH) to yield the title compound ofexample 1 (60% yield).

LC-MS (Method 2): m/z [M+H]⁺=344.1 (MW calc.=343.33); R_(t)=0.72 min.

Synthesis Example 2N-(2,4-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 2a)

To a solution of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate(2.0 g) in CH₃CN (47 mL) was added phosphorus(V) oxybromide (18.3 g) andthe mixture was heated to 80° C. for 18 h. The reaction mixture waschilled in an ice bath and sat. sodium carbonate solution was added. Themixture was extracted with EtOAc, the combined organic layers were driedand the volatiles were removed under reduced pressure to yield thedesired product.

LC-MS (Method 2): m/z [M+H]⁺=219.0 (MW calc.=219.04); R_(t)=0.45 min.

Intermediate 2b)

A solution of intermediate 2a (515 mg), 2,5-dimethoxyphenylboronic acid(642 mg) and Pd(dppf)Cl₂.CH₂Cl₂ (105 mg) in a mixture of THF (15 mL) andsodium carbonate solution (2 M, 3 mL) was heated in a microwave(Biotage®) to 100° C. for 1.5 h. The mixture was chilled, the layersseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried and the volatiles were removed under reducedpressure. The residue was purified by chromatography (Interchim®cartridge 50SiHP/25 g, Cy/EtOAc) to yield the desired compound (77%yield).

LC-MS (Method 2): m/z [M+H]⁺=277.1 (MW calc.=276.29); R_(t)=0.62 min.

Intermediate 2c)

A solution of intermediate 2b (307 mg) in dioxane (2 mL) was treatedwith aqueous LiOH solution (2 M, 0.5 mL) and the mixture was stirred at70° C. for 1 h. HCl (1 M) was added and the mixture was extracted withEtOAc. The combined organic layers were dried and the volatiles wereremoved under reduced pressure to yield the desired compound (93%yield).

LC-MS (Method 2): m/z [M+H]⁺=263.3 (MW calc.=262.26); R_(t)=0.68 min.

N-(2,4-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 2

To a solution of intermediate 2c (50 mg) and 2,4-difluoroaniline (29 mg)in dry N,N-dimethyl formamide (2.2 mL) were consecutively addedO-(7-Aza-1H-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (91 mg) and N,N-diisopropylethylamine (114 μL) andthe mixture was stirred at ambient temperature for 18 h. The solutionwas poured into sodium bicarbonate solution and was extracted withEtOAc. The organic layer was washed with water and was dried and thevolatiles were removed under reduced pressure. The residue was purifiedby chromatography (Interchim® cartridge50SiHP/12 g, Cy/EtOAc) to yieldthe title compound of example 2 (55% yield).

LC-MS (Method 2): m/z [M+H]⁺=374.1 (MW calc.=373.35); R_(t)=0.80 min.

Synthesis Example 35-(2-Ethoxy-5-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 3a)

A solution of intermediate 2a (506 mg) in dioxane (10 mL) was treatedwith LiOH solution (2 M, 1 mL) and the mixture was stirred at 70° C. for1 h. HCl (1 M) was added and the mixture was extracted with EtOAc. Thecombined organic layers were dried and the volatiles were removed underreduced pressure to yield the desired compound (84% yield).

LC-MS (Method 2): m/z [M+H]⁺=205.0 (MW calc.=205.01); R_(t)=0.31 min.

Intermediate 3b)

Intermediate 3b was prepared in analogy to the preparation of the titlecompound of example 1 through the reaction of intermediate 3a (400 mg)with 3-fluoropyridin-4-amine (248 mg) (78% yield).

LC-MS (Method 2): m/z [M+H]⁺=299.0 (MW calc.=299.10); R_(t)=0.52 min.

5-(2-Ethoxy-5-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 3

The title compound of example 3 was prepared in analogy to thepreparation of intermediate 2b through the reaction of intermediate 3b(100 mg) with 2-ethoxy-5-methoxyphenylboronic acid (115 mg) (49% yield).

LC-MS (Method 2): m/z [M+H]⁺=371.2 (MW calc.=370.38); R_(t)=0.74 min.

Synthesis Example 4N-(2,6-Difluoro-phenyl)-5-(2-ethoxy-5-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 4a)

Intermediate 4b was prepared in analogy to the preparation of the titlecompound of example 1 through the reaction of intermediate 3a (700 mg)with 2,6-difluoroaniline (445 mg) (42% yield).

LC-MS (Method 2): m/z [M+H]⁺=316.0 (MW calc.=316.10); R_(t)=0.77 min.

N-(2,6-Difluoro-phenyl)-5-(2-ethoxy-5-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 4

The title compound of example 4 was prepared in analogy to thepreparation of intermediate 2b through the reaction of intermediate 4a(120 mg) with 2-ethoxy-5-methoxyphenylboronic acid (134 mg) (42% yield).

LC-MS (Method 2): m/z [M+H]⁺=388.1 (MW calc.=387.38); R_(t)=0.78 min.

Synthesis Example 55-(2,5-Difluoro-phenyl)-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 5 was prepared in analogy to thepreparation of intermediate 2b through the reaction of intermediate 4a(150 mg) with 2,5-difluorophenylboronic acid (135 mg) (57% yield).

LC-MS (Method 2): m/z [M+H]⁺=350.1 (MW calc.=349.28); R_(t)=0.72 min.

Synthesis Example 6N-(2,6-Difluoro-phenyl)-5-[2-fluoro-5-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 6 was prepared in analogy to thepreparation of intermediate 2b through the reaction of intermediate 4a(150 mg) with 2-Fluoro-5-(trifluoromethyl)benzeneboronic acid (177 mg)(20% yield).

LC-MS (Method 2): m/z [M+H]⁺=400.1 (MW calc.=399.29); R_(t)=0.80 min.

Synthesis Example 7N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide

Intermediate 7a)

A solution of intermediate 2a (500 mg), 2-(trifluoromethyl)beneneboronicacid (650 mg), PEPPSI™-Ipr (77 mg) and potassium carbonate (939 mg) indioxane (10 mL) were heated to 120° C. for 18 h. The mixture waschilled, filtered and the volatiles were removed under reduced pressure.The residue was purified by chromatography (Interchim®cartridge50SiHP/12 g, Cy/EtOAc) to yield the desired compound (55%yield).

LC-MS (Method 2): m/z [M+H]⁺=285.2 (MW calc.=284.23); R_(t)=0.83 min.

Intermediate 7b)

Intermediate 7b was prepared in analogy to the preparation ofintermediate 3a starting from intermediate 7a (550 mg) (70% yield).

LC-MS (Method 2): m/z [M+H]⁺=271.1 (MW calc.=270.21); R_(t)=0.55 min.

N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide Example 7

The title compound of example 7 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 7b (190 mg) with 2,6-difluoroaniline (93 mg) (44% yield).

LC-MS (Method 2): m/z [M+H]⁺=382.1 (MW calc.=381.30); R_(t)=0.76 min.

Synthesis Example 8N-(2,6-Difluoro-phenyl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 8a)

Intermediate 8a was prepared in analogy to the preparation ofintermediate 2b through the reaction of intermediate 2a (396 mg) with5-methoxy-2-(trifluoromethoxy)phenylboronic acid (766 mg) (53% yield).

LC-MS (Method 2): m/z [M+H]⁺=331.2 (MW calc.=330.26); R_(t)=0.90 min.

Intermediate 8b)

Intermediate 8b was prepared in analogy to the preparation ofintermediate 3a starting from intermediate 8a (318 mg) (94% yield).

LC-MS (Method 2): m/z[M+H]⁺=317.1 (MW calc.=316.23); R_(t)=0.82 min.

N-(2,6-Difluoro-phenyl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 8

The title compound of example 8 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 8b (285 mg) with 2,6-difluoroaniline (60 mg) (24% yield).

LC-MS (Method 2): m/z [M+H]⁺=428.1 (MW calc.=427.32); R_(t)=0.82 min.

Synthesis Example 9N-(3-Fluoro-pyridin-4-yl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 9 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 8b (143 mg) with 3-fluoropyridin-4-amine (52 mg) (65%yield).

LC-MS (Method 2): m/z [M+H]⁺=411.1 (MW calc.=410.32); R_(t)=0.80 min.

Synthesis Example 10N-(2,6-Difluoro-phenyl)-5-(5-fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 10 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction of5-(5-fluoro-2-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (201mg) with 2,6-difluoroaniline (105 mg) (22% yield).

LC-MS (Method 2): m/z [M+H]⁺=362.1 (MW calc.=361.32); R_(t)=0.73 min.

Synthesis Example 115-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 11a)

To a solution of 1-Bromo-2-Chloro-4-(trifluoromethoxy)benzene (300 mg)in dry THF (1.3 mL) was added isopropylmagnesium chloride lithiumchloride complex solution (1.3 M in THF, 1.0 mL) at 0° C. and theresulting mixture was stirred at ambient temperature for 2 h. Trimethylborate (244 μL) was added at 0° C. and the reaction mixture was stirredat ambient temperature for 1 h. HCl (0.1 M, 1 mL) was added and themixture was extracted with EtOAc. The combined organic layers were driedand the volatiles were removed under reduced pressure to yield thedesired compound (77% yield).

5-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 11

The title compound of example 11 was prepared in analogy to thepreparation of intermediate 2b through the reaction of intermediate 3b(90 mg) with intermediate 11a (160 mg) (49% yield).

LC-MS (Method 2): m/z[M+H]⁺=415.1 (MW calc.=414.05); R_(t)=0.85 min.

Synthesis Example 125-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 12 was prepared in analogy to thepreparation of intermediate 2b through the reaction of intermediate 4a(90 mg) with intermediate 11a (137 mg) (49% yield).

LC-MS (Method 2): m/z [M+H]⁺=432.1 (MW calc.=431.74); R_(t)=0.86 min.

Synthesis Example 135-(2,5-Dimethoxyphenyl)-N-(2-fluoro-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

To a solution of intermediate 2c (105 mg) and2-fluoro-4-(methylsulfonyl)aniline (151 mg) in dry N,N-dimethylformamide (2 mL) were consecutively addedO-(7-Aza-1H-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (190 mg) and N,N-diisopropylethylamine (103 mg) andthe mixture was stirred at 50° C. for 18 h. The volatiles were removedunder reduced pressure and the residue was purified by preparative HPLC(40% yield)

LC-MS (Method 2): m/z [M+H]⁺=434.1 (MW calc.=433.45); R_(t)=0.73 min.

Synthesis Example 145-(2,5-Dimethoxyphenyl)-1-methyl-N-[3-(trifluoromethyl)-pyridin-4-yl]-1H-pyrazole-3-carboxylicacid amide

The title compound of example 14 was prepared in analogy to thepreparation of the title compound of example 13 through the reaction ofintermediate 2c (105 mg) with 2-(trifluoromethyl)aniline (129 mg) (43%yield).

LC-MS (Method 2): m/z [M+H]⁺=407.1 (MW calc.=406.36); R_(t)=0.84 min.

Synthesis Example 15N-(3-Cyano-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 15 was prepared in analogy to thepreparation of the title compound of example 13 through the reaction ofintermediate 2c (105 mg) with 4-aminonicotinonitrile (95 mg) (31%yield).

LC-MS (Method 2): m/z [M+H]⁺=364.1 (MW calc.=363.37); R_(t)=0.73 min.

Synthesis Example 165-(2,5-Dimethoxyphenyl)-1-methyl-N-(4-methyl-pyridin-3-yl)-1H-pyrazole-3-carboxylicacid amide

The title compound of example 16 was prepared in analogy to thepreparation of the title compound of example 13 through the reaction ofintermediate 2c (105 mg) with 4-methylpyridin-3-amine (87 mg) (75%yield).

LC-MS (Method 2): m/z [M+H]⁺=353.1 (MW calc.=352.39); R_(t)=0.50 min.

Synthesis Example 175-(2,5-Dimethoxyphenyl)-N-(4,6-dimethyl-pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 17 was prepared in analogy to thepreparation of the title compound of example 13 through the reaction ofintermediate 2c (105 mg) with 4,6-dimethylpyridin-3-amine (98 mg) (71%yield).

LC-MS (Method 2): m/z [M+H]⁺=367.1 (MW calc.=366.41); R_(t)=0.50 min.

Synthesis Example 185-(2,5-Dimethoxyphenyl)-1-methyl-N-(5-methyl-pyrimidin-4-yl)-1H-pyrazole-3-carboxylicacid amide

The title compound of example 18 was prepared in analogy to thepreparation of the title compound of example 13 through the reaction ofintermediate 2c (105 mg) with 5-methylpyrimidin-4-amine (87 mg) (20%yield).

LC-MS (Method 2): m/z [M+H]⁺=354.2 (MW calc.=353.15); R_(t)=0.61 min.

Synthesis Example 195-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 19 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 2c (390 mg) with 3-fluoropyridin-4-amine (192 mg) (24%yield).

LC-MS (Method 2): m/z [M+H]⁺=357.2 (MW calc.=356.35); R_(t)=0.68 min.

Synthesis Example 205-(2,5-Dimethoxyphenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1H-pyrazole-3-carboxylicacid amide

To a solution of intermediate 2c (100 mg) in CH₂Cl₂ (7 mL) wereconsecutively added N,N-Diisopropylethylamine (140 μL),3-methylpyridin-4-amine (40 mg) and bromotripyrrolidinophosphoniumhexafluorophosphate (230 mg) and the mixture was stirred at ambienttemperature for 2 h. The volatiles were removed under reduced pressureand the residue was purified by column chromatography (Interchim®cartridge50SiHP/25 g, Cy/EtOAc) to yield the desired compound (84%yield).

LC-MS (Method 2): m/z [M+H]⁺=353.2 (MW calc.=352.39); R_(t)=0.48 min.

Synthesis Example 21N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 21 was prepared in analogy to thepreparation of the title compound of example 13 through the reaction ofintermediate 2c (29 mg) with 2,6-difluoroaniline (17 mg) (45% yield).

LC-MS (Method 2): m/z [M+H]⁺=374.1 (MW calc.=373.35); R_(t)=0.72 min.

Synthesis Example 225-(5-Chloro-2-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 22a)

A solution of 1-(5-chloro-2-hydroxyphenyl)ethanone (3.4 g) in acetone(40 mL) was added potassium carbonate (8.2 g) and the mixture wasstirred at ambient temperature for 1 h. Methyl iodide (3.7 g) was addedand the reaction mixture was stirred at ambient temperature for 15 h.The suspension was filtered and the volatiles were removed under reducedpressure. The residue was dissolved in Et₂O and was washed with water.The organic layer was dried and the volatiles were removed under reducedpressure to yield the desired compound (90% yield).

Intermediate 22b)

A solution of intermediate 22a (3.24 g) in Et₂O (150 mL) was treated at−78° C. with lithium bis(trimethylsilyl)amide (1 m in THF, 19.8 mL) andwas stirred at this temperature for 45 min. A solution of di-tert-butyloxalate (4.38 g) in Et₂O was added and the mixture was stirred atambient temperature for 20 h and at 60° C. for 3 h. The mixture wastreated with 1 M HCl (145 mL) and the aqueous layer was extracted withEtOAc. The combined organic layers were dried and the volatiles wereremoved under reduced pressure. The residue was purified bychromatography (SiO₂, 400 g, Cy/CHCl₃) to yield the desired compound(65% yield).

Intermediate 22c)

A suspension of intermediate 22b (3.3 g) in ethanol (50 mL) was treatedwith methyl hydrazine (830 μL) at 0° C. and the mixture was stirred at80° C. for 1 h. The volatiles were removed under reduced pressure andthe residue was purified by chromatography (SiO₂, 400 g, Cy/EtOAc) toyield the desired compound (10% yield).

LC-MS (Method 1): m/z [M+H]⁺=323.2 (MW calc.=322.79); R_(t)=4.2 min.

Intermediate 22d)

A solution of intermediate 22c (341 mg) in CH₂Cl₂ (4 mL) was treatedwith trifluoroacetic acid (3 mL) and was stirred at ambient temperaturefor 2 h. The volatiles were removed under reduced pressure to yield thedesired compound (87% yield).

5-(5-Chloro-2-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 22

The title compound of example 22 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 22d (297 mg) with 3-fluoropyridin-4-amine (132 mg) (40%yield).

LC-MS (Method 2): m/z [M+H]⁺=361.1 (MW calc.=360.77); R_(t)=0.73 min.

Synthesis Example 235-(5-Chloro-2-methyl-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 23a)

Methyl magnesium bromide (3 M, 19.7 mL) was added to a solution of5-chloro-2-methylbenzonitrile (4.0 g) in dry THF (20 mL) and the mixturewas stirred at 65° C. for 15 h. Saturated ammonium chloride solution wasadded and the mixture was extracted with EtOAc. The combined organiclayers were dried and the volatiles were removed under reduce pressure.The residue was treated with 4 M HCl, stirred overnight and wasextracted with EtOAc. The combined organic layers were dried and thevolatiles were removed under reduce pressure to yield the desiredcompound (69% yield).

Intermediate 23b)

Sodium (465 mg) was dissolved in dry ethanol (25 mL) and subsequentlysolutions of diethyl oxalate (2.91 g) in dry Et₂O (10 mL) andintermediate 23a (3.05 g) in Et₂O (10 mL) were added. The reactionmixture was stirred at ambient temperature for 3d followed by additionof 1 N aqueous HCl and extraction with EtOAc. The combined organiclayers were dried and the solvent removed under reduced pressure toyield crude material of the desired product (95% yield).

Intermediate 23c)

Intermediate 23c was prepared in analogy to the preparation ofintermediate 22c through the reaction of intermediate 23b (2.3 g) withmethyl hydrazine (660 μL) (42% yield).

Intermediate 23d)

A solution of intermediate 23c (1 g) in THF (8.5 mL) was treated with 2M LiOH (4.3 mL) and the resulting mixture was stirred at ambienttemperature overnight. The mixture was treated with 2 M HCl and wasextracted with EtOAc. The combined organic layers were dried and thevolatiles were removed under reduced pressure to yield the desiredcompound (91% yield).

5-(5-Chloro-2-methyl-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 23

The title compound of example 23 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 23d (410 mg) with 3-fluoropyridin-4-amine (203 mg) (40%yield).

LC-MS (Method 2): m/z [M+H]⁺=345.1 (MW calc.=344.77); R_(t)=0.77 min.

Synthesis Example 24N-(3-Fluoro-pyridin-4-yl)-5-(4-methoxy-2-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 24a)

Intermediate 24a was prepared in analogy to the preparation ofintermediate 22a starting from 1-(4-hydroxy-2-methylphenyl)ethanone (5g) (93% yield).

Intermediate 24b)

Intermediate 24b was prepared in analogy to the preparation ofintermediate 23b starting from intermediate 24a (3 g) (90% yield).

Intermediate 24c)

Intermediate 23c was prepared in analogy to the preparation ofintermediate 22c through the reaction of intermediate 24b (4.3 g) withmethyl hydrazine (1.27 mL) (43% yield).

Intermediate 24d)

Intermediate 24d was prepared in analogy to the preparation ofintermediate 23d starting from intermediate 24c (950 mg) (82% yield).

N-(3-Fluoro-pyridin-4-yl)-5-(4-methoxy-2-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 24

The title compound of example 24 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 24d (350 mg) with 3-fluoropyridin-4-amine (168 mg) (51%yield).

LC-MS (Method 2): m/z [M+H]⁺=341.1 (MW calc.=340.35); R_(t)=0.70 min.

Synthesis Example 255-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1,4-dimethyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 25a)

A solution of 2,5-dimethoxybenzoic acid (5.00 g) in thionyl chloride (20mL) was heated to 70° C. for 1 h. The volatiles were removed underreduced pressure and the residue was dissolved in CH₂Cl₂ (20 mL). Thissolution was added to a solution of N,O-dimethylhydroxylaminehydrochloride (2.95 g) and NEt₃ (4.12 mL) in CH₂Cl₂ (40 mL) at 0° C. andthe resulting mixture was stirred at ambient temperature overnight.Saturated ammonium chloride solution was added and the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed withsaturated sodium bicarbonate solution and brine and were dried. Thevolatiles were removed under reduced pressure to yield the desiredproduct (80% yield).

Intermediate 25b)

Ethyl magnesium bromide (3 M in Et₂O, 5 mL) was added to a solution ofintermediate 25a (1.94 g) in THF (40 mL) at 0° C. and the resultingmixture was stirred at ambient temperature overnight. The reactionmixture was treated with 20% HCl (70 mL) and was extracted with EtOAc.The combined organic layers were washed with brine and dried. Thevolatiles were removed under reduced pressure to yield the desiredcompound (77%).

Intermediate 25c)

Intermediate 25c was prepared in analogy to the preparation ofintermediate 23b starting from intermediate 25b (1.48 g) (73% yield).

LC-MS (Method 1): m/z [M+H]⁺=295.2 (MW calc.=294.30); R_(t)=3.4 min.

Intermediate 25d)

Intermediate 25d was prepared in analogy to the preparation ofintermediate 22c through the reaction of intermediate 24b (4.3 g) withmethyl hydrazine (1.27 mL) (33% yield).

Intermediate 25e)

Intermediate 25e was prepared in analogy to the preparation ofintermediate 23d starting from intermediate 25d (276 mg) (83% yield).

5-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1,4-dimethyl-1H-pyrazole-3-carboxylicacid amide Example 25

The title compound of example 25 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 25e (210 mg) with 3-fluoropyridin-4-amine (93 mg) (28%yield).

LC-MS (Method 2): m/z [M+H]⁺=371.2 (MW calc.=370.38); R_(t)=0.73 min.

Synthesis Example 265-(5-Chloro-2-methyl-phenyl)-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 26 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 23d (168 mg) with 2,6-difluoroaniline (90 mg) (28% yield).

LC-MS (Method 2): m/z [M+H]⁺=362.1 (MW calc.=361.77); R_(t)=0.81 min.

Synthesis Example 275-(2,5-Dimethoxyphenyl)-1-methyl-N-(o-tolyl)-1H-pyrazole-3-carboxylicacid amide

A solution of intermediate 2c (100 mg) and o-toluidine (39 mg) in drytoluene (2 mL) was treated with trimethyl aluminum (2 M in heptane, 0.18mL) and was heated to 110° C. for 1 h. The mixture was chilled and 1 MHCl (2 mL) was added. The layers were separated and the aqueous layerwas extracted with EtOAc. The combined organic layers were dried and thevolatiles were removed under reduced pressure. The residue was purifiedby column chromatography (Interchim® cartridge 15SiHP/4 g, Cy/EtOAc) toyield the title compound (79% yield).

LC-MS (Method 2): m/z [M+H]⁺=352.2 (MW calc.=351.40); R_(t)=0.79 min.

Synthesis Example 285-(5-Chloro-2-methyl-phenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1H-pyrazole-3-carboxylicacid amide

To a solution of intermediate 23d (100 mg) in CH₂Cl₂ (7 mL) were at 0°C. consecutively added N,N-diisopropyl ethylamine (140 μL),3-methylpyridin-4-amine (40 mg) and bromotripyrrolidino phosphoniumhexafluorophosphate (230 mg) and the resulting mixture was stirred atambient temperature for 2 h. The volatiles were removed under reducedpressure and the residue was purified by column chromatography(Interchim® cartridge 15SiHP/25 g, Cy/EtOAc) to yield the desiredcompound (84% yield).

LC-MS (Method 2): m/z [M+H]⁺=341.1 (MW calc.=340.81); R_(t)=0.57 min.

Synthesis Example 29N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-H-pyrazole-3-carboxylicacid amide

Intermediate 29a)

Intermediate 29a was prepared in analogy to the preparation ofintermediate 23a starting from 2-methyl-5-(trifluoromethyl)benzonitrile(5.00 g) (75% yield).

Intermediate 29b)

Intermediate 29b was prepared in analogy to the preparation ofintermediate 23b starting from intermediate 29a (2.06 g) (91% yield).

LC-MS (Method 1): m/z [M+H]⁺=303.2 (MW calc.=302.25); R_(t)=4.0 min.

Intermediate 29c)

Intermediate 29c was prepared in analogy to the preparation ofintermediate 22c through the reaction of intermediate 29b (3.1 g) withmethyl hydrazine (793 μL) (18% yield).

LC-MS (Method 1): m/z [M+H]⁺=313.2 (MW calc.=312.29); R_(t)=3.8 min.

Intermediate 29d)

Intermediate 29d was prepared in analogy to the preparation ofintermediate 23d starting from intermediate 29c (580 mg) (89% yield).

LC-MS (Method 1): m/z [M+H]⁺=285.2 (MW calc.=284.23); R_(t)=3.5 min.

N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide Example 29

The title compound of example 29 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 29d (234 mg) with 3-fluoropyridin-4-amine (102 mg) (67%yield).

LC-MS (Method 2): m/z [M+H]⁺=379.1 (MW calc.=378.32); R_(t)=0.81 min.

Synthesis Example 30N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide

The title compound of example 30 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 29d (234 mg) with 2,6-difluoroaniline (91 μL) (46% yield).

LC-MS (Method 2): m/z [M+H]⁺=396.1 (MW calc.=395.33); R_(t)=0.82 min.

Synthesis Example 31N-(2,6-Difluoro-4-methoxy-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

To a solution of intermediate 2b (72 mg) in dry toluene (2 mL) wereconsecutively added 2,6-difluoro-4-methoxyaniline (48 mg) and trimethylaluminium (2 M in heptane, 0.15 mL) and the resulting mixture was heatedto 110° C. for 1 h. The mixture was chilled and 1 M HCl (2 mL) wasadded. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were dried and the volatileswere removed under reduced pressure. The residue was purified throughwashing with Et₂O to give the desired compound (86% yield).

LC-MS (Method 2): m/z [M+H]⁺=404.1 (MW calc.=403.38); R_(t)=0.74 min.

Synthesis Example 325-(2,5-Dimethoxyphenyl)-N-(2-fluoro-6-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 32 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 2c (100 mg) with 2-fluoro-6-methylaniline (47 mg) (61%yield).

LC-MS (Method 2): m/z [M+H]⁺=370.2 (MW calc.=369.39); R_(t)=0.74 min.

Synthesis Example 335-(2,5-Dimethoxyphenyl)-N-(2-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 33 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 2c (100 mg) with 2-fluoroaniline (42 mg) (64% yield).

LC-MS (Method 2): m/z [M+H]⁺=356.1 (MW calc.=355.36); R_(t)=0.80 min.

Synthesis Example 34N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 34 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 2c (100 mg) with 3,5-difluoropyridin-4-amine (42 mg) (64%yield).

LC-MS (Method 2): m/z [M+H]⁺=375.1 (MW calc.=374.34); R_(t)=0.67 min.

Synthesis Example 35N-(2-Chloro-6-fluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 35 was prepared in analogy to thepreparation of the title compound of example 31 through the reaction ofintermediate 2b (72 mg) with 2-chloro-6-fluoroaniline (44 mg) (67%yield).

LC-MS (Method 2): m/z [M+H]⁺=390.1 (MW calc.=389.81); R_(t)=0.76 min.

Synthesis Example 365-[2-Chloro-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 36a)

Intermediate 36a was prepared in analogy to the preparation ofintermediate 23b starting from1-(2-chloro-5-(trifluoromethyl)phenyl)ethanone (5.00 g) (99% yield).

Intermediate 36b)

A solution of intermediate 36a (3.00 g) in N,N-dimethyl acetamide (37mL) was treated with concentrated HCl (1.2 mL) and methyl hydrazine (579μL) and the resulting mixture was stirred at ambient temperature for 18h. EtOAc was added and the mixture was washed with water. The organiclayer was dried and the volatiles were removed under reduced pressure.The residue was purified by column chromatography (Interchim® cartridge50SiHP/80 g, Cy/EtOAc) to yield the desired compound (55% yield).

LC-MS (Method 1): m/z [M+H]⁺=333.2 (MW calc.=332.71); R_(t)=3.8 min.

5-[2-Chloro-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 36

The title compound of example 36 was prepared in analogy to thepreparation of the title compound of example 31 through the reaction ofintermediate 36b (700 mg) with 2,6-difluoroaniline (105 μL) (69% yield).

LC-MS (Method 2): m/z[M+H]⁺=416.1 (MW calc.=415.74); R_(t)=0.82 min.

Synthesis Example 37N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-ethyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 37a)

Intermediate 37a was prepared in analogy to the preparation ofintermediate 23b starting from 1-(2,5-dimethoxyphenyl)ethanone (9.00 g)(99% yield).

Intermediate 37b)

A solution of intermediate 37a (2.00 g) in dry toluene (28 mL) wastreated with BF₃.Et₂O (2.03 g) and the resulting mixture was stirred atambient temperature for 16 h. The volatiles were removed under reducedpressure and the residue was purified trough washing with Et₂O to yieldthe desired compound (96% yield).

Intermediate 37c)

A solution of intermediate 37b (1.1 g) in acetonitrile (22 mL) wastreated with ethyl hydrazine (726 mg) and the resulting mixture wasstirred at ambient temperature for 30 min. The volatiles were removedunder reduced pressure and the residue was purified by columnchromatography (Interchim® cartridge 50SiHP/40 g, Cy/EtOAc) to yield thedesired compound (38% yield).

LC-MS (Method 1): m/z [M+H]⁺=305.3 (MW calc.=304.34); R_(t)=3.6 min.

N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-ethyl-1H-pyrazole-3-carboxylicacid amide Example 37

The title compound of example 37 was prepared in analogy to thepreparation of the title compound of example 31 through the reaction ofintermediate 37c (100 mg) with 2,6-difluoroaniline (51 mg) (41% yield).

LC-MS (Method 2): m/z [M+H]⁺=388.1 (MW calc.=387.38); R_(t)=0.77 min.

Synthesis Example 385-[2-Cyano-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

A solution of the title compound of example 36 (335 mg), potassiumcyanide (54 mg), N,N,N′,N′-tetra-methylethylen diamine (24 μL),palladium(II) acetate (3.3 mg) and 1,5-bis(diphenylphosphino)pentane (14mg) in dry toluene (1.4 mL) was heated to 160° C. for 1 h. Potassiumcyanide (54 mg), N,N,N′,N′-tetra-methylethylen diamine (24 μL),palladium(II) acetate (3.3 mg) and 1,5-bis(diphenylphosphino)pentane (14mg) were added again and the mixture was heated to 160° C. for 2 h. Themixture was chilled and diluted with EtOAc. The organic layer was washedwith water, was dried and the volatiles were removed under reducedpressure. The residue was purified by column chromatography (Interchim®cartridge 30SiHP/12 g, Cy/EtOAc) to yield the desired compound (64%yield).

LC-MS (Method 2): m/z [M+H]⁺=407.1 (MW calc.=406.31); R_(t)=0.74 min.

Synthesis Example 394-Chloro-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 39a)

Intermediate 39a was prepared in analogy to the preparation ofintermediate 22c through the reaction of intermediate 37a (1.0 g) withmethyl hydrazine (210 μL) (72% yield).

LC-MS (Method 1): m/z [M+H]⁺=291.2 (MW calc.=290.31); R_(t)=3.5 min.

Intermediate 39b)

To a solution of intermediate 39a (747 mg) in dry CH₂Cl₂ (37 mL) wasadded sulfuryl chloride (347 mg) and the resulting mixture was stirredat ambient temperature for 1 h. The volatiles were removed under reducedpressure and the residue was purified by column chromatography(Interchim® cartridge 50SiHP/25 g, CH₂Cl₂/MeOH) to yield the desiredcompound (74% yield).

LC-MS (Method 1): m/z [M+H]⁺=325.2 (MW calc.=324.76); R_(t)=3.6 min.

4-Chloro-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 39

The title compound of example 39 was prepared in analogy to thepreparation of the title compound of example 31 through the reaction ofintermediate 39b (81 mg) with 2,6-difluoroaniline (39 mg) (81% yield).

LC-MS (Method 2): m/z [M+H]⁺=408.1 (MW calc.=407.80); R_(t)=0.77 min.

Synthesis Example 404-Chloro-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 40a)

Intermediate 49a was prepared in analogy to the preparation ofintermediate 23d starting from intermediate 39b (150 mg) (99% yield).

4-Chloro-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 40

The title compound of example 40 was prepared in analogy to thepreparation of the title compound of example 1 through the reaction ofintermediate 40a (138 mg) with 3-fluoropyridin-4-amine (93 mg) (79%yield).

LC-MS (Method 2): m/z [M+H]⁺=391.1 (MW calc.=390.80); R_(t)=0.72 min.

Synthesis Example 41N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1H-pyrazole-3-carboxylicacid amide

Intermediate 41a)

To a solution of intermediate 37a (500 mg) in EtOH (7 mL) was added(4-methoxybenzyl)hydrazine dihydrorchloride (675 mg) and the resultingmixture was stirred at ambient temperature for 18 h. The volatiles wereremoved under reduced pressure and the residue was dissolved in EtOAc.The organic layer was washed with 1 M HCl and with saturated sodiumbicarbonate solution, was dried and the volatiles were removed underreduced pressure to yield the desired compound (95% yield)

LC-MS (Method 1): m/z [M+H]⁺=397.3 (MW calc.=396.44); R_(t)=3.8 min.

Intermediate 41b)

Intermediate 41b was prepared in analogy to the preparation of the titlecompound of example 31 through the reaction of intermediate 41a (200 mg)with 2,6-difluoroaniline (61 μL) (97% yield).

LC-MS (Method 1): m/z [M+H]⁺=480.3 (MW calc.=479.48); R_(t)=3.8 min.

N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1H-pyrazole-3-carboxylicacid amide Example 41

A solution of intermediate 41b (130 mg) in trifluoroacetic acid (1.7 mL)was heated to 60° C. for 3 h. The volatiles were removed under reducedpressure and the residue was purified through washing with Et₂O to yieldthe desired compound (62% yield).

LC-MS (Method 2): m/z [M+H]⁺=360.1 (MW calc.=359.33); R_(t)=0.67 min.

Synthesis Example 42N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-ethyl-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 42a)

To solution of 2,5-dimethoxybenzonitrile (1.5 g) in dry Et₂O (7 mL) wasadded propyl magnesium chloride (2 M in Et₂O, 9.2 mL) and the resultingmixture was heated to 40° C. for 2 h. The mixture was chilled and 4 MHCl (9 mL) was carefully added and it was stirred at ambient temperaturefor 16 h. The mixture was extracted with EtOAc, the combined organiclayers were washed with water, were dried and the volatiles were removedunder reduced pressure. The residue was purified by columnchromatography (Interchim® cartridge 15SiHP/120 g, Cy/EtOAc) to yieldthe desired compound (57% yield).

LC-MS (Method 1): m/z [M+H]⁺=209.3 (MW calc.=208.25); R_(t)=3.5 min.

Intermediate 42b)

Intermediate 42b was prepared in analogy to the preparation ofintermediate 23b starting from intermediate 42a (1.08 g) (34% yield).

LC-MS (Method 1): m/z [M+H]⁺=307.2 (MW calc.=308.33); R_(t)=3.6 min.

Intermediate 42c)

Intermediate 42c was prepared in analogy to the preparation ofintermediate 22c through the reaction of intermediate 42b (524 mg) withmethyl hydrazine (98 μL) (50% yield).

LC-MS (Method 1): m/z [M+H]⁺=319.3 (MW calc.=318.37); R_(t)=3.7 min.

N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-ethyl-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 42

The title compound of example 42 was prepared in analogy to thepreparation of the title compound of example 31 through the reaction ofintermediate 42c (80 mg) with 2,6-difluoroaniline (39 mg) (49% yield).

LC-MS (Method 2): m/z [M+H]⁺=402.2 (MW calc.=401.41); R_(t)=0.82 min.

Synthesis Example 43N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-(hydroxylmethyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 43a)

Methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (2.0 g) was added at0° C. to a solution of phosphorus(V) oxychloride (13.7 g) in dry DMF (3g) and the mixture was heated to 120° C. for 4 h. After cooling toambient temperature the reaction was quenched by the addition of icewater (100 mL) and the suspension was stirred for 30 min. Theprecipitated solid formed was isolated through filtration and was washedwith water to yield the desired compound (56% yield).

LC-MS (Method 2): m/z [M+H]⁺=203.2 (MW calc.=202.60); R_(t)=2.3 min.

Intermediate 43b)

A degassed solution of intermediate 43a (1.4 g),2,5-dimethoxyphenylboronic acid (1.9 g), cesium fluoride (3.1 g) andbis(triphenylphosphine)palladium(II) dichloride (242 mg) in drydimethoxyethane (100 mL) was stirred under an argon atmosphere at 85° C.for 4 h. The mixture was chilled, filtered and the volatiles wereremoved under reduced pressure. The residue was purified by columnchromatography (Interchim® cartridge 50SiHP/120 g, CH/EtOAc) to yieldthe desired compound (76% yield).

LC-MS (Method 1): m/z [M+H]⁺=305.2 (MW calc.=304.30); R_(t)=3.1 min.

Intermediate 43c)

To a solution of intermediate 43b (500 mg) and 2,6-difluoroaniline (354mg) in dry THF (27 mL) was added lithium bis(trimethylsilyl)amide (1 Min hexane, 2.5 mL) at ambient temperature and the solution was stirredat 60° C. for 2 h. The mixture was chilled and the volatiles wereremoved under reduced pressure. The residue was purified by columnchromatography (Interchim® cartridge 30SiHP/40 g, Cy/EtOAc) to yield thedesired compound (64% yield).

LC-MS (Method 1): m/z [M+H]⁺=402.2 (MW calc.=401.36); R_(t)=3.6 min.

N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 43

To a solution of intermediate 43c (100 mg) in dry MeOH (1 mL) was addedsodium borohydrid (11 mg) and the mixture was stirred at ambienttemperature for 20 min. The volatiles were removed under reducedpressure and the residue was dissolved in 1 M HCl and was extracted withCH₂Cl₂. The combined organic layers were dried and the volatiles wereremoved under reduced pressure to yield the desired compound (75%yield).

LC-MS (Method 2): m/z [M+H]⁺=404.1 (MW calc.=403.38); R_(t)=0.69 min.

Synthesis Example 444-Amino-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 44a)

Ammonium nitrate was added to a solution of ethyl1-methyl-1H-pyrazole-3-carboxylate (460 mg) in trifluoroacetic acid (5mL) and the mixture was stirred at ambient temperature for 2 h. Thevolatiles were removed under reduced pressure and the residue wastreated with water and was extracted with CH₂Cl₂. The combined organiclayers were dried and the volatiles were removed under reduced pressure.The residue was purified through washing with Et₂O to yield the desiredcompound (90% yield).

LC-MS (Method 1): m/z [M+H]⁺=200.2 (MW calc.=199.16); R_(t)=2.4 min.

Intermediate 44b)

A degassed solution of intermediate 44a (480 mg),2-bromo-1,4-dimethoxybenzene (1.04 g), palladium acetate (54 mg),di(1-adamantyl)-n-butylphosphine (130 mg) and potassium acetate (490 mg)in N,N-dimethyl acetamide (7 mL) was stirred under an argon atmosphereat 150° C. for 2 h. The volatiles were removed under reduced pressureand the residue was dissolved in water and was extracted with CH₂Cl₂.The combined organic layers were dried and the volatiles were removedunder reduced pressure. The residue was purified by columnchromatography (SiO₂/50 g, Cy/2-propanol) to yield the desired compound(31% yield).

LC-MS (Method 1): m/z [M+H]⁺=336.2 (MW calc.=335.31); R_(t)=3.4 min.

Intermediate 44c)

Intermediate 44c was prepared in analogy to the preparation ofintermediate 43c through the reaction of intermediate 44b (200 mg) with2,6-difluoroaniline (110 mg) (92% yield).

LC-MS (Method 1): m/z [M+H]⁺=419.2 (MW calc.=418.35); R_(t)=3.3 min

4-Amino-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 44

A mixture of intermediate 44c (210 mg) and 5% palladium on charcoal (110mg) in MeOH (10 mL) was stirred under a hydrogen atmosphere (1 bar) atambient temperature for 1 h. The suspension was filtered and thevolatiles were removed under reduced pressure. The residue was purifiedby column chromatography (SiO₂/20 g, CH₂Cl₂/MeOH/NH₃) to yield thedesired compound (88% yield).

LC-MS (Method 2): m/z [M+H]⁺=389.2 (MW calc.=388.37); R_(t)=0.68 min.

Synthesis Example 455-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 45a)

4,4′-Di-tert-butyl-2,2′-dipyridyl (194 mg) was added to a solution of(1,5-Cyclooctadiene)(methoxy)-iridium(I) dimer (241 mg) andpinacolborane (4.13 g) in pentane (21 mL) and the mixture was stirredfor 20 min at ambient temperature. Then a solution of1-methyl-1H-pyrazole-3-carboxylate (3.05 g) in pentane (14 mL) and THF(7 mL) was added and the solution was stirred at ambient temperature for3 d. The volatiles were removed under reduced pressure and the residuewas purified by chromatography (SiO₂, methylene chloride/methanol) toyield the desired product (78% yield).

Intermediate 45b)

A degassed solution of intermediate 45a (900 mg),2-bromo-1-chloro-4-(trifluoromethoxy)benzene (885 mg), lithium hydroxide(83 mg) and bis(tri-tert-butylphosphine)palladium(0) (84 mg) in dry DMFwas stirred under an argon atmosphere at 90° C. for 30 min. Thevolatiles were removed under reduced pressure and the residue waspurified by column chromatography (Interchim® cartridge 50SiHP/80 g,Cy/EtOAc) to yield the desired compound (72% yield).

LC-MS (Method 1): m/z [M+H]⁺=349.2 (MW calc.=348.70); R_(t)=3.9 min.

Intermediate 45c)

A degassed solution of intermediate 45b (580 mg), potassium cyclopropyltrifluoroborate (379 mg), palladium acetate (37 m),di(1-adamantyl)-n-butylphosphine (119 mg) and cesium carbonate intoluene (12 mL) and water (5 mL) was stirred at 100° C. for 16 h. Themixture was chilled and the layers were separated. The aqueous layer wasextracted with EtOAc and the combined organic layers were dried and thevolatiles were removed under reduced pressure. The residue was purifiedby column chromatography (Interchim® cartridge 30SiHP/40 g, Cy/EtOAc) toyield the desired compound (61% yield).

LC-MS (Method 1): m/z [M+H]⁺=355.2 (MW calc.=354.32); R_(t)=4.0 min.

5-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 45

The title compound of example 45 was prepared in analogy to thepreparation of intermediate 43c through the reaction of intermediate 45c(115 mg) with 2,6-difluoroaniline (54 mg) (80% yield).

LC-MS (Method 2): m/z [M+H]⁺=438.1 (MW calc.=437.36); R_(t)=0.90 min.

Synthesis Example 465-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(3,5-difluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 46 was prepared in analogy to thepreparation of intermediate 43c through the reaction of intermediate 45c(115 mg) with 3,5-difluoropyridin-4-amine (55 mg) (79% yield).

LC-MS (Method 2): m/z [M+H]⁺=439.1 (MW calc.=438.35); R_(t)=0.86 min.

Synthesis Example 475-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

The title compound of example 47 was prepared in analogy to thepreparation of intermediate 43c through the reaction of intermediate 45c(115 mg) with 3-fluoropyridin-4-amine (55 mg) (84% yield).

LC-MS (Method 2): m/z [M+H]⁺=421.1 (MW calc.=420.36); R_(t)=0.90 min.

Synthesis Example 484-Amino-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 48a)

Intermediate 48a was prepared in analogy to the preparation ofintermediate 43c through the reaction of intermediate 44b (490 mg) with3-fluoropyridin-4-amine (213 mg) (58% yield).

LC-MS (Method 1): m/z [M+H]⁺=402.2 (MW calc.=401.35); R_(t)=3.3 min

4-Amino-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 48

A solution of intermediate 48a (300 mg) in MeOH (8 mL) was treated withacetic acid (0.7 mL) and zinc (393 mg) and the mixture was stirred atambient temperature for 20 h. The suspension was filtered and thevolatiles were removed under reduced pressure. The residue was treatedwith saturated sodium bicarbonate solution and was extracted with EtOAc.The combined organic layers were dried and the volatiles were removedunder reduced pressure. The residue was purified by columnchromatography (Interchim® cartridge 30SiHP/25 g, CH₂Cl₂/MeOH) to yieldthe desired compound (68% yield).

LC-MS (Method 2): m/z [M+H]⁺=372.1 (MW calc.=371.37); R_(t)=0.61 min.

Synthesis Example 66N-(2,6-Difluoro-phenyl)-5-(2-methoxy-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide

Intermediate 66a)

Intermediate 66a was prepared in analogy to the preparation ofintermediate 45b through the reaction of intermediate 45a (234 mg) with1-bromo-2-methoxy-4-(methylsulfonyl)-benzene (200 mg) at 110° C. for 2 h(80% yield).

LC-MS (Method 2): m/z [M+H]⁺=339.2 (MW calc.=338.1); R_(t)=0.7 min

(N-(2,6-Difluoro-phenyl)-5-(2-methoxy-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide Example 66

The title compound was prepared in analogy to the preparation ofintermediate 43c through the reaction of intermediate 66a (100 mg) with2,6-difluoroaniline (56 mg) (32% yield).

LC-MS (Method 2): m/z [M+H]⁺=422.1 (MW calc.=421.09); R_(t)=0.64 min.

Synthesis Example 67N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-4-methylamino-1H-pyrazole-3-carboxylicacid amide

Intermediate 67a)

Intermediate 67a was prepared in analogy to the preparation ofintermediate 43c through the reaction of intermediate 44b (362 mg) with4-amino-3,5-difluoropyridine (182 mg) (55% yield).

Intermediate 67b)

Intermediate 67b was prepared in analogy to the preparation of example44 through the reaction of intermediate 67a (247 mg) (94% yield).

Intermediate 67c)

To a solution of intermediate 67b (215 mg) and triethylamine (115 μL) indry CH₂Cl₂ was added 2,4-dinitrobenzolsulfonylchloride (176 mg) and themixture stirred for 24 h at ambient temperature followed by addition offurther triethylamine (60 μL) and 2,4-dinitrobenzolsulfonylchloride (88mg) and continued stirring for 6 h. Saturated NaHCO₃ solution was added,the organic layer separated and the aqueous layer extracted twice withCH₂Cl₂. The combined organic layers were dried and the volatiles wereremoved under reduced pressure. The residue was purified by columnchromatography (SiO₂, Cy/EtOAc) to yield the desired compound (43%yield).

N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-4-methylamino-1H-pyrazole-3-carboxylicacid amide Example 67

To a solution of intermediate 67c (148 mg), MeOH (97 μL) andtriphenylphosphine (125 mg) in dry CH₂Cl₂ was added diisopropylazodicarboxylate (94 μL) and the mixture was stirred for 1 h at 0° C.After addition of isopropylamine (498 μL) stirring was continued for 20h at ambient temperature. Volatiles were removed under reduced pressureand the residue was purified by column chromatography (SiO₂/Cy/EtOAc)followed by HPLC purification (250×30 mm, 5μ Phenylhexyl/35% MeCN, 65%H₂O, 0.1% TFA) to yield the title compound (39% yield).

LC-MS (Method 2): m/z [M+H]⁺=404.1 (MW calc.=403.15); R_(t)=0.67 min.

Examples 49 to 65 were synthesized in a library setup trough amidecoupling reactions between 3 carboxylic acid building blocks (BB-I,BB-II, BB-III) and commercially available amines. The structures andanalytical data of these examples are displayed in table 1.

Building Block Syntheses BB-I:5-(2-fluoro-6-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid

Intermediate-BB-Ia)

Intermediate-BB-Ia was prepared in analogy to the preparation ofintermediate 23b starting from1-(2-fluoro-6-(trifluoromethyl)phenyl)ethanone (20 g) (99% yield).

Intermediate-BB-Ib)

Intermediate-BB-Ib was prepared in analogy to the preparation ofintermediate 22c through the reaction of Intermediate-BB-Ia (29.7 g)with methyl hydrazine sulfate (16.7 g) (43% yield).

5-(2-fluoro-6-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid (BB-I)

BB-I was prepared in analogy to the preparation of intermediate 23dstarting from Intermediate-BB-Ib (29.7 g) (74% yield).

BB-II: 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

Intermediate-BB-IIa)

Intermediate-BB-IIa was prepared in analogy to the preparation ofintermediate 23b starting from 1-(2,6-difluorophenyl)ethanone (20 g)(99% yield).

Intermediate-BB-IIb)

Intermediate-BB-IIb was prepared in analogy to the preparation ofintermediate 22c through the reaction of Intermediate-BB-IIa (32.0 g)with methyl hydrazine sulfate (22.2 g) (32% yield).

5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (BB-II)

BB-II was prepared in analogy to the preparation of intermediate 23dstarting from Intermediate-BB-IIb (4.0 g) (70% yield).

BB-III: 1-methyl-5-(4-methylpyridin-3-yl)-1H-pyrazole-3-carboxylic acid

Intermediate-BB-IIIa)

Intermediate-BB-IIIa was prepared in analogy to the preparation ofintermediate 23b starting from 1-(4-methylpyridin-3-yl)ethanone (10 g)(40% yield).

Intermediate-BB-IIIb)

Intermediate-BB-IIIb was prepared in analogy to the preparation ofintermediate 22c through the reaction of Intermediate-BB-IIIa (7.0 g)with methyl hydrazine sulfate (4.2 g) (15% yield).

1-methyl-5-(4-methylpyridin-3-yl)-1H-pyrazole-3-carboxylic acid (BB-III)

BB-III was prepared in analogy to the preparation of intermediate 23dstarting from Intermediate-BB-IIIb (3.4 g) (45% yield).

Library Procedures:

Acid Chloride Method:

To a solution of BB-I-III (1 eq) in CH₂Cl₂, oxalyl chloride (1.1 eq) andDMF (cat.) were added and stirred at room temperature for 1 h. Aftercompleted formation of the acid chloride (1-2 h), the excess reagent andsolvent were evacuated, the residue diluted in dry CH₂Cl₂ and thissolution was added dropwise at 0° C. to a solution of NEt₃ (2 eq) andthe respective amine (1 eq) in CH₂Cl₂. The reaction mixture stirred atroom temperature overnight. The reaction mixture was quenched with sat.sodium bicarbonate solution (3 mL), extracted with CH₂Cl₂ and thecombined organic layers were washed with brine, dried and concentratedunder reduced pressure to give a residue that was purified bypreparative thin layer chromatography (silica gel G-G254; withrespective solvent system) to give the desired compounds.

EDC.HCl, HOBT method:

To a suspension of BB-I-III (1 eq) in CH₂Cl₂ N,N-diisopropylethylamine(3 eq) was added and the reaction mixture was stirred for 10 min.EDC.HCl (1.5 eq), HOBT (1.2 eq) were added and the reaction mixture wasstirred for 10 min. Then the respective amine (1.2 eq) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with water (3 mL), extracted with CH₂Cl₂ and thecombined organic layers were washed with brine, dried and concentratedunder reduced pressure to give a residue that was purified bypreparative thin layer chromatography (silica gel G-G254; withrespective solvent system) to give the desired compounds.

HATU Method:

To a suspension of acid BB-I-III (1 eq) in CH₂Cl₂,N,N-diisopropylethylamine (3 eq) was added and reaction mixture stirredfor 10 min. HATU (1.5 eq), was added and the reaction mixture wasstirred for 10 min. Then the respective amine (1 eq) was added and thereaction mixture stirred at room temperature overnight. The reactionmixture was diluted with water (3 mL), extracted with CH₂Cl₂ and thecombined organic layers were washed with brine, dried and concentratedunder reduced pressure to give a residue that was purified bypreparative thin layer chromatography (silica gel G-G254; withrespective solvent system) to give the target compounds.

TABLE 1

HPLC-MS (method 2) Example Nr. A₁ A₂ Name [M + H]⁺ (found) MW (calc.)t_(R) (min) 49

N-(3,5-Difluoro-pyridin-4-yl)-5-[2- fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 401.1 400.28 0.6850

N,5-Bis(2,6-difluoro-phenyl)-1- methyl-1H-pyrazole-3-carboxylic acidamide 350.1 349.28 0.74 51

N-(2,6-Difluoro-phenyl)-5-[2- fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 400.0 399.29 0.7852

N-(2-Chloro-6-methyl-phenyl)-5- (2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid amide 362.1 361.77 0.79 53

5-(2,6-Difluoro-phenyl)-N-(3- fluoro-5-methyl-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylic acid amide 347.2 346.31 0.63 54

5-[2-Fluoro-6-(trifluoromethyl)- phenyl]-1-methyl-N-[2-(trifluoro-methyloxy)-phenyl]-1H-pyrazole- 3-carboxylic acid amide 448.2 447.310.87 55

N-(2,4-Difluoro-phenyl)-5-[2- fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 400.2 399.29 0.8056

N-(2-Cyano-phenyl)-5-[2-fluoro- 6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylic acid amide 389.2 388.32 0.77 57

N-(2,4-Dichlorophenyl)-5-[2- fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 432.1 432.20 0.9258

N-(2,6-Difluoro-4-methoxy- phenyl)-5-[2-fluoro-6-(trifluoro-methyl)-phenyl]-1-methyl-1H- pyrazole-3-carboxylic acid amide 430.2429.32 0.75 59

N-(2-Fluoro-6-methyl-phenyl)-5- [2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 396.2 395.33 0.7560

5-[2-Fluoro-6-(trifluoromethyl)- phenyl]-1-methyl-N-[2-(trifluoro-methyl)-phenyl]-1H-pyrazole-3- carboxylic acid amide 432.1 431.31 0.8561

N-(2-Fluorophenyl)-5-[2-fluoro-6- (trifluoromethyl)phenyl]-1-methyl-1H-pyrazole-3-carboxylic acid amide 382.1 381.30 0.80 62

N-(3-Fluoro-pyridin-4-yl)-5-[2- fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 383.1 382.29 0.7063

N-(3-Fluoro-5-methyl-pyridin-4- yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3- carboxylic acid amide 397.2 396.31 0.6864

1-Methyl-5-(4-methyl-pyridin-3- yl)-N-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylic acid amide 361.1 360.33 0.64 65

N-(3-Fluoro-5-methyl-pyridin-4- yl)-1-methyl-5-(4-methyl-pyridin-3-yl)-1H-pyrazole-3-carboxylic acid amide 326.2 325.34 0.41Pharmacological Methods

Compounds of the invention have been tested for their effects on CRACchannels according to the following or similar procedures.

HEK Calcium Influx Assay

The effect of compounds of the invention on intracellular [Ca²⁺] wastested in the HEK293 cell line (ECACC).

HEK293 cells were cultured in DMEM/F12/Glutamax (Gibco) containing 10%FCS (Gibco), and maintained at 37° C., 5% CO₂. Cell were split twice aweek [3*10⁶ (Mon-Thu) and 1*10⁶ (Thu-Mon) cells/50 ml medium in T-175 ZKculture flasks, respectively]. Twenty four hours pre-experiment, cellswere seeded on 96 well plates (Poly-D-Lysine 96well Black/Clear Plate,BD Biocoat REF 356640) at a density of 40,000 cells/well in DMEM/F12(Gibco) containing 10% FCS (Gibco), and maintained at 37° C., 5% CO₂.

Prior to store-depletion, cell culture medium was removed and cells wereloaded with the a Calcium-sensitive fluorescent dye comprised within theCalcium-4-assay kit (Molecular Devices) in nominally Ca²⁺-free HBSbuffer (140 mM NaCl, 4 mM KCl, 0.2 mM MgCl₂, 11 mM D-glucose, and 10 mMHEPES, pH 7.4) according to manufacturer's instruction for 60 min at 37°C., 5% CO₂.

Passive depletion of intracellular Ca²⁺-stores was then triggered byemploying the SERCA inhibitor thapsigargin (2 μM final) for 10 min inthe dark (RT). To prevent immediate Ca²⁺-entry via the activatedStore-operated channels (SOCs), cells were maintained in Ca²⁺-free HBSbuffer comprising 100 μM EGTA during store-depletion.

Intracellular changes in [Ca²⁺] were subsequently monitored with theFLIPR device (Molecular Devices). In brief, baseline imaging post-storedepletion was allowed for 1 min before adjusting the extracellularbuffer to 3 mM CaCl₂. Increases in intracellular [Ca²⁺] due topre-activated SOC channels were monitored for 15 min until intracellularCa²⁺ levels had declined into a steady-state. Finally, compounds wereadministered and Ca²⁺ signals were recorded for additional 10 min.

Inhibition of endogenous SOC in HEK293 cells was quantified employingthe average Ca²⁺ signal measured from 9.5-10 min post-administration.Zero percent inhibition (MAX) was defined as the Ca²⁺ signal recordedfrom wells to which DMSO-only had been added instead of compound.Hundred percent inhibition (MIN) was defined as the signal obtained fromwells in which cells haven't been treated with TG prior to Ca²⁺ additionand to which DMSO-only had been added instead of compound. For routineIC50 determinations of compounds, 8 concentrations of a serial dilution(1:3.16) were tested, starting off from 10 μM. Reliable IC50's couldconsequently be determined only, if they were at least sub 2.5-3 μM.

Jurkat IL-2 Production Assay

The effect of compounds of the invention on Interleukin-2 (IL-2)production/release was tested in the Jurkat T cell line (ECACC) cloneE6-1.

Jurkat T cells were cultured in DMEM/F12/Glutamax (Gibco) containing 10%FCS (Gibco), and maintained at 37° C., 5% CO₂. Cell were split twice aweek [5*10⁶ (Mon-Thu) and 1*10⁷ (Thu-Mon) cells/50 ml medium in T-175 ZKculture flasks, respectively].

Prior to experiment, cells were seeded on 96 well plates (Cellstar 96Well; Cat No. 655180, Greiner bio-one) at a density of 5*10⁵ cells/wellin DMEM/F12/Glutamax (Gibco) containing 10% FCS (Gibco), and incubatedfor 60 min at 37° C., 5% CO₂. Subsequently, compounds were added andcells were allowed to incubate for 30 min at 37° C., 5% CO₂. Cells werethen stimulated with 15 μg/ml Phytohemagglutinin (PHA; Sigma) for 22hours at 37° C., 5% CO₂.

Before sampling of the supernatants, cells were spun down (200*g/5min/RT). The amount of IL-2 released into the supernatant was quantifiedwith the human IL-2 AlphaLisa kit (Perkin Elmer) according tomanufacturer's instructions. Luminescence proximity measurements werecarried out in the Synergy H4 reader (BioTek) employing the fluorescencesetting of the reader (ex: 680/30 nm; em: 620/40 nm).

Inhibition of IL-Production/Release in/from Jurkat T Cells wasQuantified as Follows:

Zero percent inhibition (MAX) was defined as the [IL-2] determined insupernatants derived from cells to which PHA & DMSO-only had been addedinstead of compound. Hundred percent inhibition (MIN) was defined as the[IL-2] determined in supernatants derived from cells that had beenpre-treated with 1 μM CyclosporineA (Sigma) before the addition of 15μg/ml PHA.

For routine IC50 determinations of compounds, 8 concentrations of aserial dilution (1:3.16) were tested, starting off from 10 μM.

TABLE 2 Exemplary compounds of the invention exhibit inhibition of theCRAC channel and inhibition of the IL-2 production in these assayswithin the following ranges: IC₅₀ values from <0.5 μM (A); 0.5-1.0 μM(B); >1.0-5.0 μM (C) and full IC₅₀ not determined (n.d.). or %inhibition @ 10 μM < 50 (C), 50-70 (B), >70 (A). Example % inhib.[@ 10μM] IC₅₀ [μM] No. FLIPR IL-2 1 A C 2 A C 3 C C 4 A B 5 B — 6 A n.d. 7 AB 8 A A 9 A C 10 A B 11 B n.d. 12 A B 13 B n.d. 14 B n.d. 15 B C 16 A C17 B C 18 C C 19 A n.d. 20 A B 21 A A 22 B n.d. 23 B n.d. 24 A n.d. 25 AB 26 A C 27 A C 28 B n.d. 29 B n.d. 30 A B 31 A A 32 A A 33 A n.d. 34 AA 35 A A 36 A A 37 B n.d. 38 B n.d. 39 A A 40 A C 41 A n.d. 42 B C 43 CC 44 B C 45 A B 46 A A 47 A C 48 A n.d. 49 A C 50 B n.d. 51 B C 52 B —53 B — 54 B — 55 B — 56 B — 57 B — 58 B — 59 A — 60 A — 61 A — 62 A — 63A — 64 A — 65 A — 66 C C 67 C C

The invention claimed is:
 1. A compound of general formula (I),

wherein R¹ denotes C₁₋₄-aliphatic residue, unsubstituted or mono- orpolysubstituted; or C₃₋₆-cycloaliphatic residue or a 3 to 7 memberedheterocycloaliphatic residue, in each case unsubstituted or mono- orpolysubstituted and in each case optionally connected via a C₁₋₄aliphatic group, which in turn may be unsubstituted or mono- orpolysubstituted; with the proviso that if R¹ represents a 3 to 7membered heterocycloaliphatic residue, said 3 to 7 memberedheterocycloaliphatic residue is connected to the remaining part of thestructure according to general formula (I) via a carbon atom of the 3 to7 membered heterocycloaliphatic residue; R² denotes H; F; Cl; Br; I;NO₂; CN; CF₃; CF₂H; CFH₂; R¹³; OH; O—R¹³; NH₂; N(H)R¹³; N(R¹³)₂; Urepresents C—R⁴ or N or N⁺—O⁻, V represents C—R⁵ or N or N⁺—O⁻, Wrepresents C—R⁶ or N or N⁺—O⁻, and X represents C—R⁷ or N or N⁺—O⁻, withthe proviso that 0, 1, 2 or 3 of variables T, U, V, W and Xindependently of one another represent(s) either N or N⁺—O⁻, whereof 0or 1 of variables T, U, V, W and X independently of one anotherrepresent(s) N⁺—O⁻ and with the proviso that at least one of U, V and Wdoes not represent N, wherein R⁴, R⁵ and R⁶ are independently of oneanother selected from the group consisting of H; F; Cl; Br; I; NO₂; CN;CF₃; CF₂H; CFH₂; CF₂C1; CFCl₂; C₁₋₈-aliphatic residue, unsubstituted ormono- or polysubstituted; C(═O)OH; C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³;C(═O)—OR¹⁴; C(═O)—N(H)(OH); C(═N—OH)—H; C(═N—OH)—R¹³; C(═N—OH)—R¹⁴;C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³; C(═N—O—R¹³)—R¹⁴; C(═O)NH₂;C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴; C(═O)—N(R¹⁴)₂;C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃; OCF₂H; OCFH₂;OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴; O—C(═O)—N(H)R¹³;O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂; O—C(═O)—N(R¹³)(R¹⁴);O—C(═O)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂; N(H)R¹⁴; N(R¹⁴)₂;N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴; NH—C(═O)—R¹³;N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³; N(R¹³)—S(═O)₂—R¹³;NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴; N(H)—C(═O)—OR¹³; N(H)—C(═O)—OR¹⁴;N(R¹³)—C(═O)—OR¹³; N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)R¹³; N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂;N(H)—C(═O)—N(R¹⁴)₂; N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂; N(R¹³)—C(═O)—N(R¹³)(R¹⁴);N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³; SCF₃; S—R¹⁴; S(═O)₂OH;S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴; S(═O)₂—OR¹³; S(═O)₂—OR¹⁴;S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂; S(═O)₂—N(H)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴);S(═O)₂—N(R^(a))(R^(b)); R³ is selected from the group consisting of F;Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R¹³; R¹⁴; C(═O)OH;C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³; C(═O)—OR¹⁴; C(═O)—N(H)(OH); C(═N—OH)—H;C(═N—OH)—R¹³; C(═N—OH)—R¹⁴; C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³;C(═N—O—R¹³)—R¹⁴; C(═O)NH₂; C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴;C(═O)—N(R¹⁴)₂; C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃;OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴;O—C(═O)—N(H)R¹³; O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂;O—C(═O)—N(R¹³)(R¹⁴); O—C(═O)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂;N(H)R¹⁴; N(R¹⁴)₂; N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴;NH—C(═O)—R¹³; N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³;N(R¹³)—S(═O)₂—R¹³; NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴; N(H)—C(═O)—OR¹³;N(H)—C(═O)—OR¹⁴; N(R¹³)—C(═O)—OR¹³; N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)R¹³; N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂;N(H)—C(═O)—N(R¹⁴)₂; N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂; N(R¹³)—C(═O)—N(R¹³)(R¹⁴);N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³; SCF₃; S—R¹⁴; S(═O)₂OH;S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴; S(═O)₂—OR¹³; S(═O)₂—OR¹⁴;S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂; S(═O)₂—N(H)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴);S(═O)₂—N(R^(a))(R^(b)); and R⁷ is selected from the group consisting ofH F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R¹³; R¹⁴;C(═O)OH; C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³; C(═O)—OR¹⁴; C(═O)—N(H)(OH);C(═N—OH)—H; C(═N—OH)—R¹³; C(═N—OH)—R¹⁴; C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³;C(═N—O—R¹³)—R¹⁴; C(═O)NH₂; C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴;C(═O)—N(R¹⁴)₂; C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃;OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴;O—C(═O)—N(H)R¹³; O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂;O—C(═O)—N(R¹³)(R¹⁴); O—C(═O)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂;N(H)R¹⁴; N(R¹⁴)₂; N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴;NH—C(═O)—R¹³; N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³;N(R¹³)—S(═O)₂—R¹³; NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴; N(H)—C(═O)—OR¹³;N(H)—C(═O)—OR¹⁴; N(R¹³)—C(═O)—OR¹³; N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)R¹³; N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂;N(H)—C(═O)—N(R¹⁴)₂; N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂; N(R¹³)—C(═O)—N(R¹³)(R¹⁴);N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³; SCF₃; S—R¹⁴; S(═O)₂OH;S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴; S(═O)₂—OR¹³; S(═O)₂—OR¹⁴;S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂; S(═O)₂—N(H)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴);S(═O)₂—N(R^(a))(R^(b)) n represents 0 or 1, wherein, if n represents 1,then K represents C—R⁹ or N or N⁺—O⁻, M represents C—R¹⁰ or N or N⁺—O⁻,Q represents C—R¹¹ or N or N⁺—O⁻, and R represents C—R¹² or N or N⁺—O⁻,with the proviso that 0, 1, 2 or 3 of variables K, M, Q and Rindependently of one another represent(s) either N or N⁺—O⁻, whereof 0or 1 of variables K, M, Q and R independently represents N⁺—O⁻, wherein,if n represents 0, then K represents C—R⁹ or N or N⁺—O⁻ or O or S or NHor N(C₁₋₄-aliphatic residue), M represents C—R¹⁰ or N or N⁺—O⁻ or O or Sor NH or N(C₁₋₄-aliphatic residue) and Q represents C—R¹¹ or N or N⁺—O⁻or O or S or NH or N(C₁₋₄-aliphatic residue), with the proviso that oneof K, M and Q represents O or S or NH or N(C₁₋₄-aliphatic residue) andthe remaining of K, M and Q independently represent C—R⁹ ‘respectivelyC—R¹⁰, respectively C—R¹¹ or N or N⁺—O⁻ and with the proviso that 0, 1or 2 of variables K, M and Q independently of one another representeither N or N⁺—O⁻, whereof 0 or 1 of variables K, M and Q representsN⁺—O⁻, wherein R⁸ is selected from F, Cl, CF₃, CF₂H, CFH₂, CH₃, CN,OCF₂H, OCFH₂, and OCF₃, and wherein R⁹, R¹⁰, R¹¹ and R¹² areindependently of one another selected from the group consisting of H; F;Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂C1; CFCl₂; R¹³; R¹⁴; C(═O)OH;C(═O)—R¹³; C(═O)R¹⁴; C(═O)—OR¹³; C(═O)—OR¹⁴; C(═O)—N(H)(OH); C(═N—OH)—H;C(═N—OH)—R¹³; C(═N—OH)—R¹⁴; C(═N—O—R¹³)—H; C(═N—O—R¹³)—R¹³;C(═N—O—R¹³)—R¹⁴; C(═O)NH₂; C(═O)—N(H)R¹³; C(═O)—N(R¹³)₂; C(═O)—N(H)R¹⁴;C(═O)—N(R¹⁴)₂; C(═O)—N(R¹³)(R¹⁴); C(═O)—N(R^(a))(R^(b)); OH; OR¹³; OCF₃;OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR¹⁴; O—C(═O)R¹³; O—C(═O)R¹⁴;O—C(═O)—N(H)R¹³; O—C(═O)—N(H)R¹⁴; O—C(═O)—N(R¹³)₂; O—C(═O)—N(R¹⁴)₂;O—C(═O)—N(R¹³)(R¹⁴); O—C(═O)—N(R^(a))(R^(b)); NH₂; N(H)R¹³; N(R¹³)₂;N(H)R¹⁴; N(R¹⁴)₂; N(R¹³)(R¹⁴); N(R^(a))(R^(b)); NH—C(═O)—R¹⁴;NH—C(═O)—R¹³; N(R¹³)—C(═O)—R¹³; N(R¹³)—C(═O)—R¹⁴; NH—S(═O)₂—R¹³;N(R¹³)—S(═O)₂—R¹³; NH—S(═O)₂—R¹⁴; N(R¹³)—S(═O)₂—R¹⁴; N(H)—C(═O)—OR¹³;N(H)—C(═O)—OR¹⁴; N(R¹³)—C(═O)—OR¹³; N(R¹³)—C(═O)—OR¹⁴; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)R¹³; N(H)—C(═O)—N(H)R¹⁴; N(H)—C(═O)—N(R¹³)₂;N(H)—C(═O)—N(R¹⁴)₂; N(H)—C(═O)—N(R¹³)(R¹⁴); N(H)—C(═O)—N(R^(a))(R^(b));N(R¹³)—C(═O)—NH₂; N(R¹³)—C(═O)—N(H)R¹³; N(R¹³)—C(═O)—N(H)R¹⁴;N(R¹³)—C(═O)—N(R¹³)₂; N(R¹³)—C(═O)—N(R¹⁴)₂; N(R¹³)—C(═O)—N(R¹³)(R¹⁴);N(R¹³)—C(═O)—N(R^(a))(R^(b)); SH; S—R¹³; SCF₃; S—R¹⁴; S(═O)₂OH;S(═O)₂—R¹³; S(═O)₂—R¹⁴; S(═O)—R¹³; S(═O)—R¹⁴; S(═O)₂—OR¹³; S(═O)₂—OR¹⁴;S(═O)₂—N(H)(R¹³); S(═O)₂—N(R¹³)₂; S(═O)₂—N(H)(R¹⁴); S(═O)₂—N(R¹³)(R¹⁴);S(═O)₂—N(R^(a))(R^(b)); wherein each R¹³ independently of each otherdenotes C₁₋₈-aliphatic residue, unsubstituted or mono- orpolysubstituted; or C₃₋₆-cycloaliphatic residue or 3 to 7 memberedheterocycloaliphatic residue, in each case unsubstituted or mono- orpolysubstituted; or C₃₋₆-cycloaliphatic residue or 3 to 7 memberedheterocycloaliphatic residue, in each case unsubstituted or mono- orpolysubstituted, and in each case connected via a C₁₋₄-aliphaticresidue, unsubstituted or mono- or polysubstituted; each R¹⁴independently of each other denotes aryl and heteroaryl residue, in eachcase independently of one another unsubstituted or mono- orpolysubstituted, or aryl and heteroaryl residue, in each caseindependently of one another unsubstituted or mono- or polysubstitutedand in each case connected via a C₁₋₄-aliphatic group, unsubstituted ormono- or polysubstituted; R^(a) and R^(b) together with the N-atomconnecting them form a 3 to 7 membered heterocyclic residue,unsubstituted or mono- or polysubstituted; optionally in the form of asingle stereoisomer or a mixture of stereoisomers, in the form of thefree compound and/or a physiologically acceptable salt thereof and/or aphysiologically acceptable solvate thereof, with the proviso that thecompound according to general formula (I) does not representN-(2-Cyanophenyl)-5-(2-methoxy-5-methylphenyl)-1-methyl-1H-pyrazole-3-carboxamide,

5-(2-Fluoro-4-methoxyphenyl)-N-(2-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxamide,

1-Ethyl-5-(2-fluoro-4-methoxyphenyl)-N-(2-fluorophenyl)-1H-pyrazole-3-carboxamide


2. A compound according to claim 1, wherein R² is selected from thegroup consisting of H; F; Cl; Br; CN; CF₃; CF₂H; CFH₂; R¹³; OH; O—R¹³;NH₂; N(H)R¹³; N(R¹³)₂, wherein R¹³ independently of each other denotesan unsubstituted or mono- or polysubstituted C₁₋₄ aliphatic residue. 3.A compound according to claim 1 wherein R¹ is selected from the groupconsisting of unsubstituted C₁₋₄-aliphatic residue and unsubstitutedcyclopropyl.
 4. A compound according to claim 1 wherein n represents 1,and K represents C—R⁹, M represents C—R¹⁰ or N or or N⁺—O⁻, Q representsC—R¹¹ and R represents C—R¹² or n represents 1, and K represents C—R⁹, Mrepresents N, Q represents C—R¹¹ and R represents N.
 5. A compoundaccording to claim 1 wherein n represents 1, R represents C—R¹², whereinR¹² is selected from the group consisting of H; CH₃; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; CH₂CH₃; CN; OH; OCH₃; OCHF₂; OCH₂F; OCHF₂; OCF₃; NH₂;NHCH₃; N(CH₃)₂; NH(C═O)CH₃; F; Cl and Br.
 6. A compound according toclaim 1 wherein n represents 1, M represents N or N⁺—O⁻ or C—R¹⁰,wherein R¹⁰ is selected from the group consisting of H; F; Cl; CN; CF₃;CF₂H; CFH₂; CF₂Cl; CFCl₂; C₁₋₈-aliphatic residue; C(═O)OH; C(═O)—NH₂;C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue.
 7. A compound according to claim 1wherein U represents C—R⁴, V represents C—R⁵, W represents C—R⁶, and Xrepresents C—R⁷.
 8. A compound according to claim 1 wherein R³ isselected from the group consisting of F; Cl; CN; CF₃; CF₂H; CFH₂; CF₂Cl;CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphatic residue; C(═O)OH; C(═O)—NH₂;C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphatic residue;C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphatic residue)₂; OH;O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphaticresidue; NH₂; N(H)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphatic residue)₂;N(H)—C(═O)—C₁₋₈-aliphatic residue; N(C₁₋₈-aliphaticresidue)-S(═O)₂—C₁₋₈-aliphatic residue; N(H)—S(═O)₂—NH₂;S(═O)₂—C₁₋₈-aliphatic residue; C₃₋₆-cycloaliphatic residue; 3 to 7membered heterocycloaliphatic residue, and X represents C—R⁷ and R⁷represents H or F or CH₃ or CF₃.
 9. A compound according to claim 1wherein R⁴, R⁵ and R⁶ are selected from the group consisting of H; F;Cl; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃;C₁₋₈-aliphatic residue; C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue;C(═O)O—C₁₋₈-aliphatic residue; C(═O)NH—C₁₋₈-aliphatic residue;C(═O)N(C₁₋₈-aliphatic residue)₂; OH; O—C₁₋₈-aliphatic residue; OCF₃;OCF₂H; OCFH₂; O—C(═O)—C₁₋₈-aliphatic residue; NH₂; N(H)—C₁₋₈-aliphaticresidue; N(C₁₋₈-aliphatic residue)₂; N(H)—C(═O)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)-S(═O)₂—C₁₋₈-aliphatic residue;N(H)—S(═O)₂—NH₂; S(═O)₂—C₁₋₈-aliphatic residue; preferably from thegroup consisting of H; F; Cl; OCH₃; OCHF₂; OCFH₂; OCF₃; CN; CH₃; CF₃;CF₂H and CFH₂.
 10. A compound according to claim 1 wherein R¹ denotesunsubstituted C₁₋₄-aliphatic residue; R² denotes H; F; Cl, OH, NH₂,NHCH₃, N(CH₃)₂, CH₂NH₂, CH₂—N(CH₃)₂, CH₂OH; or unsubstituted C₁₋₄aliphatic residue; preferably denotes H, Cl, NH₂, CH₃, CH₂OH and CH₂CH₃;U represents C—R⁴ or N, V represents C—R⁵ or N, W represents C—R⁶ or N,and X represents C—R⁷, with the proviso that 0, 1, 2 or 3 of variablesU, V, W and X independently of one another represent(s) N, and with theproviso that at least one of U, V and W does not represent N, R³ denotesF; Cl; CN; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂; cyclopropyl;unsubstituted C₁₋₄-aliphatic residue; OH or unsubstitutedO—C₁₋₄-aliphatic residue; R⁷ denotes H, F, CH₃ or CF₃; and R⁴, R⁵ and R⁶are independently selected from the group consisting of H; F; Cl; CN;CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; OCHF₂; OCFH₂; OCF₃; C₁₋₈-aliphaticresidue; C(═O)—NH₂; C(═O)—C₁₋₈-aliphatic residue; C(═O)O—C₁₋₈-aliphaticresidue; C(═O)NH—C₁₋₈-aliphatic residue; C(═O)N(C₁₋₈-aliphaticresidue)₂; OH; O—C₁₋₈-aliphatic residue; OCF₃; OCF₂H; OCFH₂;O—C(═O)—C₁₋₈-aliphatic residue; NH₂; N(H)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)₂; N(H)—C(═O)—C₁₋₈-aliphatic residue;N(C₁₋₈-aliphatic residue)-S(═O)₂—C₁₋₈-aliphatic residue;N(H)—S(═O)₂—NH₂; S(═O)₂—C₁₋₈-aliphatic residue; n represents 1, Krepresents C—R⁹ and Q represents C—R¹¹, wherein R⁹ and R¹¹ areindependently of one another selected from the group consisting of H; F;Cl; CN; CF₃; CF₂H; CFH₂; OCF₃; OCF₂H; OCFH₂; CH₃; OH; and OCH₃; and Mrepresents N or N⁺—O⁻ or C—R¹⁰, wherein R¹⁰ is selected from the groupconsisting of H; F; Cl; OCH₃; CN; CH₃; CF₃; CF₂H; CFH₂ or S(═O)₂—CH₃ Rrepresents C—R¹², wherein R¹² is selected from the group consisting ofH; CH₃; CF₃; CF₂H; CFH₂; CH₂CH₃; CN; OH; OCH₃; OCHF₂; OCH₂F; OCHF₂;OCF₃; F and Cl.
 11. A compound according to claim 1 wherein the compoundhas general formula (Iaa),

wherein R¹, R², U, V, W and X are defined as as before, R⁸ denotes F,Cl, CN, CF₃, CF₂H, CFH₂, CH₃ or O—CH₃ and K, M, Q and R independentlyrepresent N, CH or C—R^(8a), wherein R^(8a) denotes F, Cl, CN, CF₃,CF₂H, CFH₂, CH₃, CH₂CH₃, O—CH₃ or O—CH₂CH₃, with the proviso, that 0 or1 of the substituents K, M, Q and R represent N.
 12. A compoundaccording to claim 1 wherein the compound is selected from the groupconsisting of 1N-(2,6-Difluoro-phenyl)-5-(2-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 2N-(2,4-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 35-(2-Ethoxy-5-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 4N-(2,6-Difluoro-phenyl)-5-(2-ethoxy-5-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 55-(2,5-Difluoro-phenyl)-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 6N-(2,6-Difluoro-phenyl)-5-[2-fluoro-5-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 7N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide; 8N-(2,6-Difluoro-phenyl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 9N-(3-Fluoro-pyridin-4-yl)-5-[5-methoxy-2-(trifluoromethyloxy)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 10N-(2,6-Difluoro-phenyl)-5-(5-fluoro-2-methoxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 115-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 125-[2-Chloro-4-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 135-(2,5-Dimethoxyphenyl)-N-(2-fluoro-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 145-(2,5-Dimethoxyphenyl)-1-methyl-N-[3-(trifluoromethyl)-pyridin-4-yl]-1H-pyrazole-3-carboxylicacid amide; 15N-(3-Cyano-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 165-(2,5-Dimethoxyphenyl)-1-methyl-N-(4-methyl-pyridin-3-yl)-1H-pyrazole-3-carboxylicacid amide; 175-(2,5-Dimethoxyphenyl)-N-(4,6-dimethyl-pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 185-(2,5-Dimethoxyphenyl)-1-methyl-N-(5-methyl-pyrimidin-4-yl)-1H-pyrazole-3-carboxylicacid amide; 195-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 205-(2,5-Dimethoxyphenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1H-pyrazole-3-carboxylicacid amide; 21N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 225-(5-Chloro-2-methoxy-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 235-(5-Chloro-2-methyl-phenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 24N-(3-Fluoro-pyridin-4-yl)-5-(4-methoxy-2-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 255-(2,5-Dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1,4-dimethyl-1H-pyrazole-3-carboxylicacid amide; 265-(5-Chloro-2-methyl-phenyl)-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 275-(2,5-Dimethoxyphenyl)-1-methyl-N-(o-tolyl)-1H-pyrazole-3-carboxylicacid amide; 285-(5-Chloro-2-methyl-phenyl)-1-methyl-N-(3-methyl-pyridin-4-yl)-1H-pyrazole-3-carboxylicacid amide; 29N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide; 30N-(2,6-Difluoro-phenyl)-1-methyl-5-[2-methyl-5-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide; 31N-(2,6-Difluoro-4-methoxy-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 325-(2,5-Dimethoxyphenyl)-N-(2-fluoro-6-methyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 335-(2,5-Dimethoxyphenyl)-N-(2-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 34N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 35N-(2-Chloro-6-fluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 365-[2-Chloro-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 37N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-ethyl-1H-pyrazole-3-carboxylicacid amide; 385-[2-Cyano-5-(trifluoromethyl)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 394-Chloro-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 404-Chloro-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 41N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1H-pyrazole-3-carboxylicacid amide; 42N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-ethyl-1-methyl-1H-pyrazole-3-carboxylicacid amide; 43N-(2,6-Difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-4-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 444-Amino-N-(2,6-difluoro-phenyl)-5-(2,5-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 455-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 465-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(3,5-difluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 475-[2-Cyclopropyl-5-(trifluoromethyloxy)-phenyl]-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 484-Amino-5-(2,5-dimethoxyphenyl)-N-(3-fluoro-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 49N-(3,5-Difluoro-pyridin-4-yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 50N,5-Bis(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acidamide; 51N-(2,6-Difluoro-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 52N-(2-Chloro-6-methyl-phenyl)-5-(2,6-difluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 535-(2,6-Difluoro-phenyl)-N-(3-fluoro-5-methyl-pyridin-4-yl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 545-[2-Fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-N-[2-(trifluoromethyloxy)-phenyl]-1H-pyrazole-3-carboxylicacid amide; 55N-(2,4-Difluoro-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 56N-(2-Cyano-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 57N-(2,4-Dichlorophenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 58N-(2,6-Difluoro-4-methoxy-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 59N-(2-Fluoro-6-methyl-phenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 605-[2-Fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-N-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide; 61N-(2-Fluorophenyl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 62N-(3-Fluoro-pyridin-4-yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 63N-(3-Fluoro-5-methyl-pyridin-4-yl)-5-[2-fluoro-6-(trifluoromethyl)-phenyl]-1-methyl-1H-pyrazole-3-carboxylicacid amide; 641-Methyl-5-(4-methyl-pyridin-3-yl)-N-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxylicacid amide; 65N-(3-Fluoro-5-methyl-pyridin-4-yl)-1-methyl-5-(4-methyl-pyridin-3-yl)-1H-pyrazole-3-carboxylicacid amide; 66N-(2,6-Difluoro-phenyl)-5-(2-methoxy-4-methylsulfonyl-phenyl)-1-methyl-1H-pyrazole-3-carboxylicacid amide; 67N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dimethoxyphenyl)-1-methyl-4-methylamino-1H-pyrazole-3-carboxylicacid amide; optionally in the form of the free compound and/or aphysiologically acceptable salt thereof and/or a physiologicallyacceptable solvate thereof.
 13. A pharmaceutical composition comprisingat least one compound according claim 1 and optionally one or moresuitable, pharmaceutically compatible auxiliaries and/or, ifappropriate, one or more further pharmacologically active compounds. 14.A method for the treatment of one or more disorders selected from thegroup consisting of inflammatory disorders and/or autoimmune diseasesand/or allergic disorders comprising administering to a patient in needthereof an effective amount of a compound according to claim
 1. 15. Amethod for the treatment of psoriasis and/or psoriatic arthritis and/orrheumatoid arthritis and/or inflammatory bowel disease and/or asthmaand/or allergic rhinitis comprising administering to a patient in needthereof an effective amount of a compound according to claim
 1. 16. Acompound according to claim 2 wherein R² is selected from the groupconsisting of H, Cl, NH₂, CH₃, CH₂OH and CH₂CH₃.
 17. A compoundaccording to claim 3 wherein R¹ denotes CH₃ or CH₂CH₃.
 18. A compoundaccording to claim 6 wherein R¹⁰ is selected from the group consistingof the group consisting of H; F; Cl; OCH₃; CN; CH₃; CF₃; CF₂H; CFH₂ andS(═O)₂—CH.
 19. A compound according to claim 9 wherein R⁴, R⁵ and R⁶ areselected from the group consisting of the group consisting of H; F; Cl;OCH₃; OCHF₂; OCFH₂; OCF₃; CN; CH₃; CF₃; CF₂H and CFH₂.